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  • 101.
    Laskar, Amit
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Eilertsen, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Yuan, Xi-Ming
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    SPION primes THP1 derived M2 macrophages towards M1-like macrophages2013In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 441, no 4, p. 737-742Article in journal (Refereed)
    Abstract [en]

    Potentially, cellular iron regulates functional plasticity in macrophages yet; interaction of functionally polarized macrophages with iron-oxide nanoparticles has never been studied. We found that monocyte differentiation alters cellular ferritin and cathepsin L levels and induces functional polarization in macrophages. Iron in super paramagnetic iron-oxide nanoparticle (SPION) induces a phenotypic shift in THP1 derived M2 macrophages towards a high CD86+ macrophage subtype. This phenotypic shift was accompanied by up-regulated intracellular levels of ferritin and cathepsin L in M2 macrophages, which we found as a characteristic hallmark of M1 macrophages. Atherogenic oxysterols reduce phagocytic activity in both macrophage subtypes and thus these cells may escape detection by ironoxide nanoparticles (INPs) in-vivo.

  • 102.
    Laskar, Amit
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Miah, Sayem
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G G
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Prevention of 7beta-hydroxycholesterol-induced cell death by mangafodipir is mediated through lysosomal and mitochondrial pathways2010In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, no 640, p. 124-128Article in journal (Refereed)
    Abstract [en]

    Mangafodipir, a MRI contrast agent, has been used as a viability marker in patients with myocardial infarction and showed vascular relaxation effect. It confers myocardial protection against oxidative stress. However mechanisms underlying such protection have not yet been investigated. In this investigation we first studied whether mangafodipir inhibits apoptosis induced by 7beta-hydroxycholesterol (7betaOH), a cytotoxic cholesterol oxidation product found in atherosclerotic lesions in humans and in heart of ethanol-fed rats. We then focused on whether mangafodipir influences the production of reactive oxygen species, lysosomal and mitochondrial membrane permeabilities in the cell model. Our results revealed that pre-treatment with mangafodipir (400microM) protected against cellular reactive oxygen species production, apoptosis, and permeabilization of lysosomal and mitochondrial membranes induced by 7betaOH. In conclusion, a novel effect of mangafodipir on 7betaOH-induced apoptosis is via reduction of cellular reactive oxygen species and stabilization of lysosomal and mitochondrial membranes. This is the first report to show the additional cytoprotective effect of mangafodipir, which may suggest possible use of the drug.

  • 103.
    Lesen, Eva
    et al.
    Nordic School for Public Health.
    Sandstrom, Tatiana Z
    Nordic School for Public Health.
    Carlsten, Anders
    Medical Prod Agency.
    Jönsson, Anna K
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Mardby, Ann-Charlotte
    University of Gothenburg.
    Andersson Sundell, Karolina
    Nordic School for Public Health.
    A comparison of two methods for estimating refill adherence to statins in Sweden: the RARE project2011In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 20, no 10, p. 1073-1079Article in journal (Refereed)
    Abstract [en]

    Purpose To analyse and compare refill adherence to statins estimated with two different methods with a focus on sensitivity to definitions. less thanbrgreater than less thanbrgreater thanMethods Individuals aged 18-85 years who filled a statin prescription for the first time in 1.5 years during 1 January-30 June 2007 were followed until emigration or death or until 2 years after their first statin purchase. The data were collected via linkage between the Swedish Prescribed Drug Register, the National Patient Register and the Total Population Register. Days supply was estimated based on amount dispensed and prescribed dosage. Refill adherence was estimated with the continuous measure of medication acquisition (CMA) and the maximum gap method (cut-off 45days). The impact of altering definitions, for example, regarding hospitalisations, length of observation period and management of overlapping supply, was analysed. less thanbrgreater than less thanbrgreater thanResults The study included 36661 individuals (mean age 64 years, 47% women). The median proportion of days with statins was 95%, and 76% were classified as adherent with a cut-off at andgt;= 80% with CMA. With the maximum gap method, 65% were adherent. Disregarding hospitalisations did not alter the results. Emigration or death at least one year after statin initiation was associated with a lower adherence with both methods, and a shorter observation period and adding overlapping supply to the subsequent prescription increased the adherence estimates. less thanbrgreater than less thanbrgreater thanConclusions The choice of method and definitions, particularly regarding the management of overlapping supplies and the length of observation period, has a substantial impact on estimates of refill adherence to statins.

  • 104.
    Levander, Louise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Ryden, I
    Kalmar County Hospital.
    Påhlsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Effects of alpha 1-acid Glycoprotein Fucosylation on its Ca2+ Mobilizing Capacity in Neutrophils2009In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 69, no 5, p. 412-420Article in journal (Refereed)
    Abstract [en]

    We recently showed that the acute-phase protein alpha(1)-acid glycoprotein (AGP) induces rises in cytosolic calcium concentration, [Ca2+](i,) in neutrophils through sialic acid dependent interactions with the neutrophil receptors siglec-5 and/or siglec-14. Whereas both siglec-5 and siglec-14 have a relatively broad specificity for sialylated oligosaccharide structures, including both structures with terminal alpha 2-3 or alpha 2-6 linked sialic acid, there is a markedly reduced affinity to the fucosylated epitope sialyl Lewis x (SLe(x)). Increased fucosylation, leading to increased expression of SLe(x) on AGP is commonly associated with inflammatory conditions. In the present study, we investigated whether an increased SLe(x) expression would affect the Ca2+-mobilizing effect of AGP. AGP with elevated fucose content isolated from patients with untreated chronic joint inflammation showed a decreased [Ca2+](i) modulatory effect on neutrophils compared to normally fucosylated AGP. Furthermore a hyperfucosylated AGP form produced by in vitro fucosylation, that consequently had an elevated expression of SLe(x), could not elicit a [Ca2+](i) increase in neutrophils. The role of the carbohydrate portion of AGP in modulating neutrophil responses was further strengthened by showing that synthetic glycoconjugates carrying oligosaccharides with terminal alpha 2-3 or alpha 2-6 linked sialic acid were able to mimic the Ca2+-mobilizing effect of AGP whereas a synthetic glycoconjugate carrying SLe(x) was not. Based on these data, we conclude that increased fucosylation can alter the ability of AGP to induce neutrophil signalling and further supports an important role of the oligosaccharide chains of AGP in the modulation of leukocyte functions during an inflammatory process.

  • 105.
    Levander, Louise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Peter
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Påhlsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Alpha-1-acid glycoprotein interacts with the neutrophilproteins S100A8 and S100A9Manuscript (preprint) (Other academic)
    Abstract [en]

    The acute phase protein α1-acid glycoprotein (AGP) has been indicated tobind to neutrophils and to affect neutrophil functions. In the presentinvestigation neutrophil proteins interacting with AGP was studied. Twolow molecular weight proteins were isolated from neutrophil lysates byaffinity chromatography on a column with immobilized AGP. The proteinswere identified as the calcium-binding, myeloid related proteins S100A8and S100A9 using mass spectrometry and Western blot analyses. Theinteraction was further confirmed using a biotin affinity-tagging procedure.The interaction between AGP and S100A8/A9 was sensitive to EDTAindicating a calcium-dependent binding. Desialylation andhyperfucosylation of AGP did not affect its binding to S100A8/A9.

  • 106.
    Levander, Louise
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Peter
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Påhlsson, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Alpha1-acid glycoprotein is a carrier of hydroxyeicosatetraenoic acids – role in calcium mobilization ofpolymorphonuclear granulocytesManuscript (preprint) (Other academic)
    Abstract [en]

    We have previously shown that α1-acid glycoprotein (AGP) induces rises incytosolic calcium concentration, [Ca2+]i, in human polymorphonuclear granulocytes(PMN) and that this effect is enhanced by prior pre-sensitization of PMN with theanti L-selectin antibody DREG-56. AGP is a known carrier of several lipophilicsubstances. This study was designed to determine whether lipids bound to AGP areinvolved in the induction of [Ca2+]i mobilization in PMN. We found that delipidatedAGP elicited a smaller rise in [Ca2+]i in DREG-56 pretreated PMN compared tonative AGP and that lipids extracted from AGP provoked an increase in [Ca2+]i thatwas potentiated by L-selectin pre-engagement with DREG-56. Similarly to whatwas previously found for AGP, the increase in [Ca2+]i produced by the AGP lipidextract involved activation of src-tyrosine kinases and PI3-kinases. The AGP lipidextract was analyzed by high-performance thin layer chromatography. Individualbands were extracted from the plate and their Ca2+ mobilizing activity wasanalyzed. One band contained activity and was further analyzed by electro-spraytandem mass spectrometry. The active band contained a mixture of hydroxyeicosatetraenoic acids (HETEs) with 12-HETE being one of the major components.Pharmacological studies indicated that the AGP lipid extract acted through theleukotriene B4-receptor type II, BLT2. This study supports the hypothesis that someof the immunomodulatory properties that have been attributed to AGP may beconnected to lipids carried by this plasma protein.

  • 107.
    Li, Wei
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Johnson, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, Xi-Ming
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    7beta-hydroxycholesterol induces natural killer cell death via oxidative lysosomal destabilization2009In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 43, no 11, p. 1072-1079Article in journal (Refereed)
    Abstract [en]

    Peripheral natural killer (NK) cells are reduced in patients with coronary artery disease and highly susceptible to apoptosis induced by oxidized lipids including 7beta-hydroxycholesterol (7betaOH) in vitro. The present study aimed to further explore the mechanisms behind 7betaOH-mediated cytotoxicity to human NK cells. Human NK cells were purified and treated with 7betaOH in different concentrations and times. Cell death, lysosomal and mitochondrial permeabilization and reactive oxygen species (ROS) production were then analysed. The 7betaOH induced time and dose dependent apoptosis and necrosis in human NK cells, which was preceded by loss of lysosomal integrity and enhanced ROS production. At later time points, the mitochondrial membrane permeability in 7betaOH-treated cells was significantly increased. The findings indicate that 7betaOH induces human NK cell death through early lysosomal permeabilization and consequent oxidative stress. The data further suggest that 7betaOH may induce immune disturbances in clinical settings such as atherosclerosis.

  • 108.
    Li, Wei
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Johnson, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, Xi-Ming
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    7ß-hydroxycholesterol induces natural killer cell death via oxidative lysosomal destabilization2009In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 43, no 11, p. 1072-1079Article in journal (Refereed)
    Abstract [en]

    Peripheral natural killer (NK) cells are reduced in patients with coronary artery disease and highly susceptible to apoptosis induced by oxidized lipids including 7beta-hydroxycholesterol (7betaOH) in vitro. The present study aimed to further explore the mechanisms behind 7betaOH-mediated cytotoxicity to human NK cells. Human NK cells were purified and treated with 7betaOH in different concentrations and times. Cell death, lysosomal and mitochondrial permeabilization and reactive oxygen species (ROS) production were then analysed. The 7betaOH induced time and dose dependent apoptosis and necrosis in human NK cells, which was preceded by loss of lysosomal integrity and enhanced ROS production. At later time points, the mitochondrial membrane permeability in 7betaOH-treated cells was significantly increased. The findings indicate that 7betaOH induces human NK cell death through early lysosomal permeabilization and consequent oxidative stress. The data further suggest that 7betaOH may induce immune disturbances in clinical settings such as atherosclerosis.

  • 109.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Ivanova, S.
    Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States.
    Tracey, K.J.
    Laboratory of Biomedical Science, North Shore-LIE Research Institute, Manhasset, NY 11030, United States.
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin2003In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 371, no 2, p. 429-436Article in journal (Refereed)
    Abstract [en]

    Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH3, protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.

  • 110.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Östblom, Mattias
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Xu, Lihua
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Hellsten, A.
    Leanderson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine . Östergötlands Läns Landsting, Centre for Medicine, Pain and Rehabilitation Centre.
    Liedberg, Bo
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Eaton, J.W.
    James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Cytocidal effects of atheromatous plaque components: The death zone revisited2006In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 20, no 13, p. 2281-2290Article in journal (Refereed)
    Abstract [en]

    Objective: Earlier we suggested that atheroma lesions constitute a "death zone" containing toxic materials that may cause dysfunction and demise of invading macrophages to prevent the removal of plaque materials. Here we have assessed the cytotoxic effects of nonfractionated gruel and insoluble (ceroid-like) material derived from advanced human atheroma. Methods and Results: The insoluble material within advanced atherosclerotic plaque was isolated following protease K digestion and extensive extraction with aqueous and organic solvents. FTIR, Raman, and atomic absorption spectroscopy suggested that, despite its fluorescent nature, this material closely resembled hydroxyapatite and dentin, but also contained a significant amount of iron and calcium. When added to J774 cells and human macrophages in culture, this insoluble substance was phagocytosed, and progressive cell death followed. However, an even more cytotoxic activity was found in the atheromatous "gruel" that contains abundant carbonyls/aldehydes. Cell death caused by both crude gruel and ceroid could be blocked by preincubating cells with the lipophilic iron chelator salicylaldehyde isonicotinoyl hydrazone, apoferritin, BAPTA/AM, or sodium borohydride, indicating that cellular iron, calcium, and reactive aldehyde(s) are responsible for the observed cytotoxicity. Conclusions: Toxic materials within atheromatous lesions include both ceroid and even more cytotoxic lipidaceous materials. The cytotoxic effects of these plaque components may help explain the persistence of atherosclerotic lesions. © FASEB.

  • 111.
    Lindstrom, Mai
    et al.
    Luleå University.
    Tärning, Eva
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Ekedahl , Anders
    Nationall Corporation of Swedish Pharmacies.
    Overestimation of the risk for ADRs due to the presentation in the package leaflets2009In: PHARMACY WORLD and SCIENCE,ISSN 0928-1231: Volume 31, Issue 1, 2009, Vol. 31, no 1, p. 53-54Conference paper (Refereed)
  • 112.
    Ljungberg, Liza
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Angiotensin-Converting Enzyme: Effects of Smoking and Other Risk Factors for Cardiovascular Diseases2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cardiovascular diseases (CVDs) are the most common cause of death in Western countries. Smoking, hypertension, diabetes mellitus and hypercholesterolemia are considered as major risk factors. However, the underlying mechanisms by which these factors cause CVDs are not entirely clear. Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin-aldosterone system, converting angiotensin I to the vasoactive peptide angiotensin II. Besides being an important factor for normal regulation of blood pressure, ACE appears to be involved in the pathogenesis of atherosclerosis. Previous studies have shown an upregulation of ACE in atherosclerotic plaques. There is genetic polymorphism in the ACE gene (ACE I/D polymorphism) which is strongly connected to the levels of ACE in plasma, but has also been associated with higher risk for cardiovascular diseases. The aim of this thesis was to investigate ACE in vitro and in vivo, in relation to cardiovascular risk factors and CVDs. The results showed that nicotine and nicotine metabolites increase ACE activity in human endothelial cells in vitro. Smoking was associated with increased plasma ACE levels. This effect might be mediated by nicotine and nicotine metabolites. These results could explain one cellular mechanism by which smoking exerts negative effect on the vascular system. Extract of oral snuff inhibited ACE in human endothelial cells and in serum, whereas extract of cigarette smoke had no effect on endothelial ACE. If these results have any physiological relevance remains to be investigated. Cardiovascular risk factors and CVDs were associated with increased levels of ACE in plasma. No association between ACE D/D genotype and CVDs was found. Based on these results we suggest that an increased level of ACE, rather than ACE genotype, is associated with increased risk for CVDs.

    List of papers
    1. Effect of Nicotine and Nicotine Metabolites on Angiotensin-Converting Enzyme in Human Endothelial Cells
    Open this publication in new window or tab >>Effect of Nicotine and Nicotine Metabolites on Angiotensin-Converting Enzyme in Human Endothelial Cells
    2008 (English)In: Endothelium, ISSN 1062-3329, E-ISSN 1029-2373, Vol. 15, no 5-6, p. 239-245Article in journal (Refereed) Published
    Abstract [en]

    Nicotine has been shown to induce endothelial dysfunction, which is an early marker of atherosclerosis. Nicotine undergoes extensive metabolism in the liver, forming a number of major and minor metabolites. There are very limited data on the effect of nicotine metabolites on the cardiovascular system. This study investigates the effects of nicotine and the nicotine metabolites, cotinine, cotinine-N-oxide, nicotine-1-N-oxide, norcotinine, trans-3-hydroxycotinine, on angiotensin-converting enzyme (ACE) in human endothelial cells. Cultured endothelial cells obtained from human umbilical cord vein (HUVECs) were stimulated with nicotine or nicotine metabolites in concentrations similar to those observed in plasma during smoking. ACE activity and expression were analyzed using commercial kits. The results showed that nicotine and nicotine metabolites can increase both activity and expression of ACE. However, a marked individual variation in the response to the drugs was observed. This variation was not associated with the ACE insertion/deletion polymorphism. Tobacco contains numerous chemical compounds, and the underlying cause for development of atherosclerosis in smokers is probably multifactorial. The results from this study could explain one cellular mechanism by which smoking exerts negative effect on the vascular system.

    Keywords
    Angiotensin-Converting Enzyme, Atherosclerosis, Endothelial Cells, Nicotine, Nicotine Metabolites, Tobacco
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16216 (URN)10.1080/10623320802487627 (DOI)
    Note
    This is an electronic version of an article published in:Liza Ljungberg and Karin Persson, Effect of Nicotine and Nicotine Metabolites on Angiotensin-Converting Enzyme in Human Endothelial Cells, 2008, Endothelium, (15), 5-6, 239-245.Endothelium is available online at informaworldTM: http://dx.doi.org/10.1080/10623320802487627Copyright: Taylor & Francishttp://www.tandf.co.uk/journals/default.aspAvailable from: 2009-04-08 Created: 2009-01-09 Last updated: 2017-12-14Bibliographically approved
    2. Is ACE level rather than ACE genotype a risk factor for cardiovascular disease?
    Open this publication in new window or tab >>Is ACE level rather than ACE genotype a risk factor for cardiovascular disease?
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) is associated with the level of ACE in plasma. However, there are large variations in plasma ACE level among individuals with the same genotype. Furthermore, ACE D/D genotype has been associated with increased risk for cardiovascular disease. The aim of this study was to investigate variations in plasma ACE levels in order to elucidate the associations between circulating ACE levels, ACE genotype, known cardiovascular risk factors and cardiovascular diseases (CVDs).

    Methods and Results: Plasma ACE levels and ACE genotype were analysed in a Swedish population consisting of 672 elderly men and women. Association between ACE-genotype, levels of circulating ACE and known cardiovascular risk factors and CVDs were analyzed. The results showed increased plasma ACE levels in individuals with hypertension (p=0.003), ischemic heart disease (p=0.03), in smokers (p=0.011) and in individuals with heredity for CVDs (p=0.031). Furthermore, treatment with ACE inhibitors increased the level of ACE in plasma (p<0.001). No association was found between D/D genotype and CVD. Instead, ischemic heart disease was more frequent among carriers of the I/I genotype (p=0.009).

    Conclusion: Although plasma ACE levels are strongly influenced by ACE genotype, there are large variations in plasma ACE level among carriers of the same genotype. Our data does not support an association between ACE D/D polymorphism and CVDs but indicates an association to increased level of ACE in the circulation, suggesting that ACE level rather than ACE genotype is the crucial factor associated with risk for CVDs.

    Keywords
    Atherosclerosis, endothelium, genetics, hypertension, smoking
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16703 (URN)
    Available from: 2009-02-12 Created: 2009-02-12 Last updated: 2017-03-27Bibliographically approved
  • 113.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Alehagen, Urban
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Björck, Hanna
    Linköping University, Department of Medicine and Health Sciences, Physiology . Linköping University, Faculty of Health Sciences.
    Länne, Toste
    Linköping University, Department of Medicine and Health Sciences, Physiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Debasso, Rachel
    Linköping University, Department of Medicine and Health Sciences, Physiology . Linköping University, Faculty of Health Sciences.
    Dahlström, Ulf
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    IS ACE LEVEL RATHER THAN ACE GENOTYPE A RISK FACTOR FOR CARDIOVASCULAR DISEASE?2009In: in JOURNAL OF HYPERTENSION, vol 27, 2009, Vol. 27, p. S455-S455Conference paper (Refereed)
    Abstract [en]

    n/a

  • 114.
    Ljungberg, Liza
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Alehagen, Urban
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Cardiology . Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Björck, Hanna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Physiology .
    Toste, Länne
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    DeBasso, Rachel
    Dahlström, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Cardiology . Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Persson, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Is ACE level rather than ACE genotype a risk factor for cardiovascular disease?Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) is associated with the level of ACE in plasma. However, there are large variations in plasma ACE level among individuals with the same genotype. Furthermore, ACE D/D genotype has been associated with increased risk for cardiovascular disease. The aim of this study was to investigate variations in plasma ACE levels in order to elucidate the associations between circulating ACE levels, ACE genotype, known cardiovascular risk factors and cardiovascular diseases (CVDs).

    Methods and Results: Plasma ACE levels and ACE genotype were analysed in a Swedish population consisting of 672 elderly men and women. Association between ACE-genotype, levels of circulating ACE and known cardiovascular risk factors and CVDs were analyzed. The results showed increased plasma ACE levels in individuals with hypertension (p=0.003), ischemic heart disease (p=0.03), in smokers (p=0.011) and in individuals with heredity for CVDs (p=0.031). Furthermore, treatment with ACE inhibitors increased the level of ACE in plasma (p<0.001). No association was found between D/D genotype and CVD. Instead, ischemic heart disease was more frequent among carriers of the I/I genotype (p=0.009).

    Conclusion: Although plasma ACE levels are strongly influenced by ACE genotype, there are large variations in plasma ACE level among carriers of the same genotype. Our data does not support an association between ACE D/D polymorphism and CVDs but indicates an association to increased level of ACE in the circulation, suggesting that ACE level rather than ACE genotype is the crucial factor associated with risk for CVDs.

  • 115.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Alehagen, Urban
    Linköping University, Department of Medicine and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    De Basso, Rachel
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Dahlström, Ulf
    Linköping University, Department of Medicine and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Länne, Toste
    Linköping University, Department of Medicine and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Circulating angiotensin-converting enzyme levels are associated with left ventricular dysfunction, but not with central aortic blood pressure, aortic augmentation or pulse pressure amplification2011Manuscript (preprint) (Other academic)
    Abstract [en]

    Aim: This study aimed to explore the link between angiotensin-converting enzyme (ACE), and left ventricular (LV) function and central hemodynamics.

    Methods and Results: The study population consisted of 672 subjects (322 men and 350 women) aged 69-87 years. LV function was evaluated semi-quantitatively by visual estimation using echocardiography. Central aortic blood pressure, aortic augmentation and pulse pressure amplification were determined in a sub-group of 422 subjects by the use of the SphygmoCor system. ACE genotype was determined by PCR and circulating ACE levels were analysed using enzyme-linked immunosorbent assay (ELISA).

    LV dysfunction was associated with higher levels of circulating ACE compared to subjects with normal LV function (p=0.007). This association remained after adjustment for factors previously shown to affect circulating ACE (ACE-genotype, age, diabetes and smoking) (p=0.036). There was a significant association between ACE level and degree of LV dysfunction (p=0.019). However, there was no association of ACE genotype or circulating ACE with central aortic blood pressure, aortic augmentation or pulse pressure amplification.

    Conclusion: Subjects with LV dysfunction have higher levels of circulating ACE compared to subjects with normal LV function. ACE might play a role in the pathogenesis of LV dysfunction and our data indicates a direct effect on the heart rather than affecting central blood pressure.

  • 116.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Björck, Hanna
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    De Basso, Rachel
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    The association between circulating angiotensin-converting enzyme and cardiovascular risk in the elderly: A cross-sectional study.2011In: jraas. Journal of the renin-angiotensin-aldosterone system, ISSN 1470-3203, E-ISSN 1752-8976, Vol. 12, no 3, p. 281-289Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: A polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with increased risk for cardiovascular disease (CVD). This polymorphism affects the level of circulating ACE, but there is great individual variation, even between those with the same genotype. Few previous studies have investigated the link between circulating ACE and cardiovascular risk. The aim of this study was to investigate this association, and to examine the relationship between ACE level, ACE genotype and CVD.

    MATERIALS AND METHODS: The study population consisted of 322 men and 350 women aged 69-87. Plasma ACE level was determined using enzyme-linked immunosorbent assay (ELISA), and ACE genotype was analysed using PCR followed by gel electrophoresis.

    RESULTS: In men, ACE levels increased with increasing number of cardiovascular risk factors (p = 0.003). There was a significant association in men between increased ACE level and both diabetes (p = 0.007) and smoking (p = 0.037).

    CONCLUSIONS: This study shows that cardiovascular risk factors (such as smoking and diabetes) are associated with higher levels of circulating ACE in men. High ACE levels may represent one of the cellular mechanisms involved in producing the vascular damage associated with cardiovascular risk factors.

  • 117.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    De Basso, Rachel
    Linköping University, Faculty of Health Sciences. Linköping University, Center for Medical Image Science and Visualization, CMIV. Linköping University, Department of Medical and Health Sciences, Physiology.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Björck, Hanna
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland.
    Impaired abdominal aortic wall integrity in elderly men carrying the angiotensin-converting enzyme D allele2011In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 42, no 3, p. 309-316Article in journal (Refereed)
    Abstract [en]

    Objective: A genetic polymorphism in the angiotensin-converting enzyme gene (ACE I/D polymorphism) has been associated with abdominal aortic aneurysm and a link between aortic aneurysm and aortic stiffness has been suggested. The aim of this study was to explore the links between ACE I/D polymorphism, circulating ACE, and abdominal aortic wall integrity as reflected by abdominal aortic wall stiffness.

    Material: The study population consisted of 406 subjects (212 men and 194 women) aged 70-88 years.

    Methods: The mechanical properties of the abdominal aorta were determined 3-4 cm proximal to the aortic bifurcation using a Wall Track System. ACE-genotype was determined by PCR followed by gel electrophoresis, and circulating ACE level was measured by ELISA.

    Results: Men carrying the ACE D allele had lower distensibility coefficient than II carriers (ID/DD 8.09 vs II 10.38, P=0.017). Multiple regression analyses showed additional associations between the ACE D allele and increased stiffness β as well as reduced cross-sectional compliance.

    Conclusion: This study showed that men carrying the ACE D allele have stiffer abdominal aortas compared to II carriers. Deranged abdominal aortic stiffness indicates impaired vessel wall integrity, which along with other local predisposing factors, may be of importance in aneurysmal disease.

  • 118.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    ACE GEnotype Determines Activity and Levels of Serum ACE but not Tissue ACE2007In: Atherosclerosis suppl, 2007, p. 1-Conference paper (Refereed)
  • 119.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effect of Nicotine and Nicotine Metabolites on Angiotensin-Converting Enzyme in Human Endothelial Cells2008In: Endothelium, ISSN 1062-3329, E-ISSN 1029-2373, Vol. 15, no 5-6, p. 239-245Article in journal (Refereed)
    Abstract [en]

    Nicotine has been shown to induce endothelial dysfunction, which is an early marker of atherosclerosis. Nicotine undergoes extensive metabolism in the liver, forming a number of major and minor metabolites. There are very limited data on the effect of nicotine metabolites on the cardiovascular system. This study investigates the effects of nicotine and the nicotine metabolites, cotinine, cotinine-N-oxide, nicotine-1-N-oxide, norcotinine, trans-3-hydroxycotinine, on angiotensin-converting enzyme (ACE) in human endothelial cells. Cultured endothelial cells obtained from human umbilical cord vein (HUVECs) were stimulated with nicotine or nicotine metabolites in concentrations similar to those observed in plasma during smoking. ACE activity and expression were analyzed using commercial kits. The results showed that nicotine and nicotine metabolites can increase both activity and expression of ACE. However, a marked individual variation in the response to the drugs was observed. This variation was not associated with the ACE insertion/deletion polymorphism. Tobacco contains numerous chemical compounds, and the underlying cause for development of atherosclerosis in smokers is probably multifactorial. The results from this study could explain one cellular mechanism by which smoking exerts negative effect on the vascular system.

  • 120.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effect of Tobacco Use on Angiotensin-Converting Enzyme in Human Endothelial Cells2008Conference paper (Other academic)
  • 121.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Nicotine and Nicotine metabolites increases ACE activity in human endothelial cells2006In: Scandinavian Cardiovascular Journal Suppl, 2006, p. 54-Conference paper (Refereed)
  • 122.
    Ljungberg, Liza
    et al.
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Eriksson, Andreas
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects of nicotine, its metabolites and tobacco extracts on human platelet function in vitro2013In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, no 2, p. 932-938Article in journal (Refereed)
    Abstract [en]

    Cigarette smoking is a leading cause of cardiovascular disease. The cardiovascular effects of smoking are probably multifactorial, including effects on platelets. Previous reports investigating the effects of nicotine and tobacco on platelet function are inconsistent.

    The present study investigated in vitro effects of nicotine, its major metabolites, tobacco extracts and extract of tobacco-free snuff on human platelets.

    None of the metabolites cotinine, cotinine-N-oxide, nicotine-1′-N-oxide or trans-3′-hydroxycotinine (0.1–10 μM) affected platelet aggregation or P-selectin expression. Nicotine (10 μM) weakly increased platelet aggregation, whereas trans-3′-hydroxycotinine (0.1 μM) and nicotine-1′-N-oxide (1–10 μM) weakly inhibited adhesion to fibrinogen. To elucidate the influence of other tobacco compounds, we investigated the impact of moist tobacco and smoke extracts on platelet function. Filtered extracts of oral snuff, cigarette smoke and tobacco free snuff inhibited platelet adhesion concentration-dependently. The inhibitory effects of tobacco extracts on platelet adhesion were independent of nicotine content and the nitric-oxide-pathway and not mediated through a platelet-nicotine-receptor.

    Taken together, tobacco extracts inhibit platelet activation during short-term in vitro challenge. As only limited effects of nicotine and nicotine metabolites were seen, the tobacco-induced platelet inhibition are likely induced by other compounds present in tobacco and tobacco free snuff.

  • 123.
    Ljungberg, Liza U.
    et al.
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    De Basso, Rachel
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Persson, Karin
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Länne, Toste
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Circulating angiotensin-converting enzyme is associated with left ventricular dysfunction, but not with central aortic hemodynamics2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 166, no 2, p. 540-541Article in journal (Refereed)
  • 124.
    Ljunggren, Stefan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Bengtsson, Torbjorn
    Orebro Univ, Sweden.
    Karlsson, Helen
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Linköping University, Faculty of Medicine and Health Sciences.
    Starkhammar Johansson, Carin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Public Dental Health Care.
    Palm, Eleonor
    Orebro Univ, Sweden.
    Nayeri, Fariba
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
    Ghafouri, Bijar
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Pain and Rehabilitation Center.
    Davies, Julia
    Malmo Univ, Sweden.
    Svensater, Gunnel
    Malmo Univ, Sweden.
    Lönn, Johanna
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Orebro Univ, Sweden; Malmo Univ, Sweden.
    Modified lipoproteins in periodontitis: a link to cardiovascular disease?2019In: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 39, no 3, article id BSR20181665Article in journal (Refereed)
    Abstract [en]

    There is a strong association between periodontal disease and atherosclerotic cardiovascular disorders. A key event in the development of atherosclerosis is accumulation of modified lipoproteins within the arterial wall. We hypothesise that patients with periodontitis have an altered lipoprotein profile towards an atherogenic form. Therefore, the present study aims at identifying modifications of plasma lipoproteins in periodontitis. Lipoproteins from ten female patients with periodontitis and gender- and age-matched healthy controls were isolated by density-gradient ultracentrifugation. Proteins were separated by 2D gel-electrophoresis and identified by map-matching or by nano-LC followed by MS. Apolipoprotein (Apo) A-I (ApoA-I) methionine oxidation, Oxyblot, total antioxidant capacity and a multiplex of 71 inflammation-related plasma proteins were assessed. Reduced levels of apoJ, phospholipid transfer protein, apoF, complement C3, paraoxonase 3 and increased levels of alpha-1-antichymotrypsin, apoA-II, apoC-III were found in high-density lipoprotein (HDL) from the patients. In low-density lipoprotein (LDL)/very LDL (VLDL), the levels of apoL-1 and platelet-activating factor acetylhydrolase (PAF-AH) as well as apo-B fragments were increased. Methionine oxidation of apoA-I was increased in HDL and showed a relationship with periodontal parameters. alpha-1 antitrypsin and alpha-2-HS glycoprotein were oxidised in LDL/VLDL and antioxidant capacity was increased in the patient group. A total of 17 inflammation-related proteins were important for group separation with the highest discriminating proteins identified as IL-21, Fractalkine, IL-17F, IL-7, IL-1RA and IL-2. Patients with periodontitis have an altered plasma lipoprotein profile, defined by altered protein levels as well as post-translational and other structural modifications towards an atherogenic form, which supports a role of modified plasma lipoproteins as central in the link between periodontal and cardiovascular disease (CVD).

  • 125.
    Lovejoy, David B
    et al.
    University of Sydney.
    Jansson, Patric J
    University of Sydney.
    Brunk, Ulf
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Wong, Jacky
    University of Sydney.
    Ponka, Prem
    Lady Davis Institute.
    Richardson, Des R
    University of Sydney.
    Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lysosomes2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 17, p. 5871-5880Article in journal (Refereed)
    Abstract [en]

    The metal-chelating compound Dp44mT is a di-2-pyridylketone thiosemicarbazone (DpT) which displays potent and selective antitumor activity. This compound is receiving translational attention, but its mechanism is poorly understood. Here, we report that Dp44mT targets lysosome integrity through copper binding. Studies using the lysosomotropic fluorochrome acridine orange established that the copper-Dp44mT complex (Cu[Dp44mT]) disrupted lysosomes. This targeting was confirmed with pepstatin A-BODIPY FL, which showed redistribution of cathepsin D to the cytosol with ensuing cleavage of the proapoptotic BH3 protein Bid. Redox activity of Cu[Dp44mT] caused cellular depletion of glutathione, and lysosomal damage was prevented by cotreatment with the glutathione precursor N-acetylcysteine. Copper binding was essential for the potent antitumor activity of Dp44mT, as coincubation with nontoxic copper chelators markedly attenuated its cytotoxicity. Taken together, our studies show how the lysosomal apoptotic pathway can be selectively activated in cancer cells by sequestration of redox-active copper. Our findings define a novel generalized strategy to selectively target lysosome function for chemotherapeutic intervention against cancer.

  • 126.
    Lyons, Paul A
    et al.
    Addenbrookes Hospital, England.
    Rayner, Tim F
    Addenbrookes Hospital, England.
    Trivedi, Sapna
    Addenbrookes Hospital, England.
    Holle, Julia U
    University Hospital Schleswig Holstein, Germany.
    Watts, Richard A
    Ipswich Hospital National Health Serv Trust, England University of E Anglia, England .
    Jayne, David R W
    Addenbrookes Hospital, England University of Cambridge, England .
    Baslund, Bo
    Copenhagen University Hospital, Denmark .
    Brenchley, Paul
    University of Manchester, England .
    Bruchfeld, Annette
    Karolinska University Hospital, Sweden .
    Chaudhry, Afzal N
    Addenbrookes Hospital, England University of Cambridge, England .
    Tervaert, Jan Willem Cohen
    Maastricht University, Netherlands .
    Deloukas, Panos
    Wellcome Trust Sanger Institute, England .
    Feighery, Conleth
    Trinity Coll Dublin, Ireland St James Hospital, Ireland .
    Gross, Wolfgang L
    University Hospital Schleswig Holstein, Germany Klinikum Bad Bramstedt, Germany .
    Guillevin, Loic
    University of Paris, France .
    Gunnarsson, Iva
    Karolinska University Hospital, Sweden .
    Harper, Lorraine
    University of Birmingham, England .
    Hruskova, Zdenka
    Charles University of Prague, Czech Republic Gen University Hospital, Czech Republic .
    Little, Mark A
    UCL, England .
    Martorana, Davide
    University Hospital, Italy .
    Neumann, Thomas
    University Hospital, Germany .
    Ohlsson, Sophie
    Karolinska Institute, Sweden Lund University, Sweden .
    Padmanabhan, Sandosh
    University of Glasgow, Scotland .
    Pusey, Charles D
    University of London Imperial Coll Science Technology and Med, England .
    Salama, Alan D
    UCL, England University of London Imperial Coll Science Technology and Med, England .
    Sanders, Jan-Stephan F
    University of Groningen, Netherlands .
    Savage, Caroline O
    GlaxoSmithKline, England .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Stegeman, Coen A
    University of Birmingham, England University of Groningen, Netherlands .
    Tesar, Vladimir
    Charles University of Prague, Czech Republic Gen University Hospital, Czech Republic .
    Vaglio, Augusto
    University Hospital, Italy .
    Wieczorek, Stefan
    Ruhr University of Bochum, Germany .
    Wilde, Benjamin
    Maastricht University, Netherlands .
    Zwerina, Jochen
    University of Erlangen Nurnberg, Germany Medical University of Vienna, Austria Medical University of Vienna, Austria .
    Rees, Andrew J
    Medical University of Vienna, Austria .
    Clayton, David G
    Addenbrookes Hospital, England.
    Smith, Kenneth G C
    Addenbrookes Hospital, England.
    Genetically Distinct Subsets within ANCA-Associated Vasculitis2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 367, no 3, p. 214-223Article in journal (Refereed)
    Abstract [en]

    BACKGROUND less thanbrgreater than less thanbrgreater thanAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegeners granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis. less thanbrgreater than less thanbrgreater thanMETHODS less thanbrgreater than less thanbrgreater thanA genomewide association study was performed in a discovery cohort of 1233 U. K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria. less thanbrgreater than less thanbrgreater thanRESULTS less thanbrgreater than less thanbrgreater thanWe found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding alpha(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P = 6.2x10(-89), P = 5.6x10(-12), and P = 2.6x10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P = 2.1x10(-8)). less thanbrgreater than less thanbrgreater thanCONCLUSIONS less thanbrgreater than less thanbrgreater thanThis study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.)

  • 127. Martensson, LGE
    et al.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    A pharmacological interaction between melatonin and the alpha(2)-adrenoceptor in cuckoo wrasse melanophores1999In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 460, p. 221-228Article in journal (Refereed)
  • 128.
    Martensson, L.G.E.
    et al.
    Mårtensson, L.G.E., Department of Zoology, Göteborg University, Box 463, SE-405 30 Göteborg, Sweden.
    Andersson, Rolf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Is Ca2+ the second messenger in the response to melatonin in cuckoo wrasse melanophores?2000In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 66, no 11, p. 1003-1010Article in journal (Refereed)
    Abstract [en]

    Pigment aggregation in melanophores of Labrus ossifagus is controlled by an a2-adrenoceptor and is somehow modulated by melatonin. The signal transduction mechanisms seem to involve both an attenuation of cAMP and an increase in intracellular Ca2+, inhibiting protein kinase A or activating a phosphatase, respectively. These effects result in dephosphorylation, which in turn induces aggregation. Various a2-adrenoceptor agonists attenuate cAMP levels or increase the concentration of intracellular Ca2+. Noradrenaline, for example, lowers cAMP but does not affect the calcium signal whereas B-HT 920, an a2-adrenoceptor specific agonist, does not induce a cAMP decrease but does appear to induce an increase in intracellular Ca2+. This later inference is drawn from experiments with BAPTA/AM, an intracellular calcium chelator, which counteracts the aggregation induced by B-HT 920. Interestingly, the very potent a2-adrenoceptor agonist medetomidine apparently activates both signal transduction pathways, which could explain its high efficacy in producing aggregation. Melatonin itself does not cause pigment aggregation, but it potentiates noradrenaline-induced aggregation. It has been suggested that melatonin receptors and a2- adrenoceptors follow the same signal transduction pathway, i.e. an attenuation of cAMP. In our experiments, melatonin did not reduce cAMP levels, instead it appears to increase Ca2+ concentration, since melatonin- potentiated aggregation was inhibited by BAPTA/AM. Thus, aggregation amplified by melatonin is probably not mediated by a further decrease in cAMP, but by the same signal transduction mechanism as B-HT 920, i.e. an increase in Ca2+. This further strengthens the suggestion that melatonin and B-HT 920 bind to the same site, but it is unclear if that particular site is on the melatonin receptor or the a2-adrenoceptor.

  • 129.
    Merkofer, M.
    et al.
    Laboratorium für Anorganische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, CH-8093 Zürich, Switzerland.
    Kissner, R.
    Laboratorium für Anorganische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, CH-8093 Zürich, Switzerland.
    Hider, R.C.
    Department of Pharmacy, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NN, United Kingdom.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Koppenol, W.H.
    Laboratorium für Anorganische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, CH-8093 Zürich, Switzerland.
    Fenton chemistry and iron chelation under physiologically relevant conditions: Electrochemistry and kinetics2006In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 19, no 10, p. 1263-1269Article in journal (Refereed)
    Abstract [en]

    The goal of iron-chelation therapy is to reduce the levels of labile plasma iron, and intravenously administered desferrioxamine is the gold standard of therapeutic agents. Hydroxypyridinones, e.g., CP20 (3-hydroxy-1,2- dimethylpyridin-4(1H)-one), are used or are under investigation as orally administered iron chelators. We determined electrode potentials of CP20, the related hydoxypyridones CP361, CP363, and CP502, and ICL670 (4-[3,5-bis(2- hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid) under physiologically relevant conditions to address the question of whether iron in the presence of these chelating agents can carry out Fenton chemistry in vivo. We found that iron(III) but not iron(II) binds tightly to both CP20 and ICL670 at pH 7 and higher, compared to nearly complete binding of 1 µM iron(II) to 10 µM desferrioxamine at pH 7.4 The electrode potentials of the hydroxypyridinones shift to more negative values with decreasing pKa values at lower concentrations of iron(III) (0.02 mM) and ligand (0.1 mM). The electrode potential of the iron-CP20 system decreases as a function of increasing pH, with a minimum near pH 10.5. We estimate an electrode potential for the ascorbyl radical/ascorbate couple under physiological conditions of +105 mV, which is higher than the electrode potential of the iron(III) complex of CP20 at all concentrations of iron. The rate of oxidation of iron(II) in the presence of CP20 by hydrogen peroxide increases with the concentrations of both ligand and peroxide. Although iron(II) is oxidized by hydrogen peroxide, the thus-formed FeIII(CP20)3 complex cannot be reduced by ascorbate. Therefore, the tight binding of iron(III) by this class of chelators prevents redox cycling. © 2006 American Chemical Society.

  • 130.
    Mohammad, Aladdin
    et al.
    Skåne University Hospital.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Prevalence of ANCA Associated Vasculitis and Polyarteritis Nodosa in Southern Sweden-Revisited 2010 in ARTHRITIS AND RHEUMATISM, vol 63, issue 10, pp S727-S7282011In: ARTHRITIS AND RHEUMATISM, Wiley-Blackwell , 2011, Vol. 63, no 10, p. S727-S728Conference paper (Refereed)
    Abstract [en]

    n/a

  • 131.
    Nilsson, Harriet M.
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Karlsson, Annika M.
    Linköping University, Department of Medicine and Care, Pharmacology. Linköping University, Faculty of Health Sciences.
    Loitto, Vesa-Matti
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Svensson, Samuel P.S.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Nitric oxide modulates intracellular translocation of pigment organelles in Xenopus laevis melanophores2000In: Cell Motility and the Cytoskeleton, ISSN 0886-1544, E-ISSN 1097-0169, Vol. 47, no 3, p. 209-218Article in journal (Refereed)
    Abstract [en]

    Pigment organelles in Xenopus laevis melanophores are used by the animal to change skin color, and they provide a good model for studying intracellular organelle transport. Movement of organelles and vesicles along the cytoskeleton is essential for many processes, such as axonal transport, endocytosis, and intercompartmental trafficking. Nitric oxide (NO) is a signaling molecule that plays a role in, among other things, relaxation of blood vessels, sperm motility, and polymerization of actin. Our study focused on the effect NO exerts on cytoskeleton-mediated transport, which has previously received little attention. We found that an inhibitor of NO synthesis, N-nitro-L-arginine methyl ester (L-NAME), reduced the melatonin-induced aggregation of the pigment organelles, melanosomes. Preaggregated melanosomes dispersed after treatment with L-NAME but not after exposure to the inactive stereoisomer (D-NAME) or the substrate for NO synthesis (L-arginine). Signal transduction by NO can be mediated through the activation of soluble guanylate cyclase (sGC), which leads to increased production of cGMP and activation of cGMP-dependent kinases (PKG). We found that both the sGC inhibitor 1H-(1,2,4) oxadiazolo(4,3-a)quinoxalin-1-one (ODQ) and the cGMP analogue 8-bromoguanosine 3′:5′-cyclic monophosphate (8-Br-cGMP) reduced melanosome aggregation, whereas the PKG inhibitor KT582 did not. Our results demonstrate that melanosome aggregation depends on synthesis of NO, and NO deprivation causes dispersion. It seems, thus, as if NO and cGMP are essential and can regulate melanosome translocation.

  • 132.
    Nilsson, Lena
    et al.
    Linköping University, Department of Medical and Health Sciences, Anesthesiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping. Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre.
    Goscinski, Tomas
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindenberger, Marcus
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Johansson, Anders
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, The Institute of Technology.
    Respiratory variations in the photoplethysmographic waveform: acute hypovolaemia during spontaneous breathing is not detected2010In: Physiological Measurement, ISSN 0967-3334, E-ISSN 1361-6579, Vol. 31, no 7, p. 953-962Article in journal (Refereed)
    Abstract [en]

    Recent studies using photoplethysmographic (PPG) signals from pulse oximeters have shown potential to assess hypovolaemia during spontaneous breathing. This signal is heavily filtered and reports are based on respiratory variations in the small pulse synchronous variation of PPG. There are stronger respiratory variations such as respiratory synchronous variation (PPGr) in the baseline of the unfiltered PPG signal. We hypothesized that PPGr would increase during hypovolaemia during spontaneous breathing. Hemodynamic and respiratory data were recorded together with PPG infrared signals from the finger, ear and forearm from 12 healthy male volunteers, at rest and during hypovolaemia created by the application of a lower body negative pressure (LBNP) of 15, 30 and 60 cmH(2)O. Hemodynamic and respiratory values changed significantly. From rest to the LBNP of 60 cmH(2)O systolic blood pressure fell from median (IQR) 116 (16) to 101 (23) mmHg, the heart rate increased from 58 (16) to 73 (16) beats min(-1), and the respiratory rate increased from 9.5 (2.0) to 11.5 (4.0) breaths min(-1). The amplitude of PPGr did not change significantly at any measurement site. The strongest effect was seen at the ear, where the LBNP of 60 cmH(2)O gave an amplitude increase from 1.0 (0.0) to 1.31 (2.24) AU. PPG baseline respiratory variations cannot be used for detecting hypovolaemia in spontaneously breathing subjects.

  • 133.
    Nilsson, Siv
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Neuropeptides in theautonomic nervous systeminfluencing uveal blood flowand aqueous humour dynamics2009In: Neuropeptides in the Eye, Kerala, India: Research Signpost , 2009, p. 147-167Chapter in book (Other academic)
    Abstract [en]

    The uveal blood vessels, especially those of the choroid, have a rich innervation from the autonomic nervous system. The superior cervical ganglion is the source of the sympathetic nerve fibres, and the facial nerve, with a synapse in the pterygopalatine ganglion, is the major parasympathetic supply in mammals. Neuropeptide YNPY) is the most abundant peptide in the sympathetic nerve fibres, whereas (vasoactive intestinal polypeptide (VIP) is the main peptide in the parasympathetic nerve fibres. Pituitary adenylate cyclase activating polypeptide (PACAP-27 and PACAP-38) and peptide histidine isoleucine (PHI/PHM) are also present in the parasympathetic fibres.

    NPY is a potent vasoconstrictor in the rabbit uvea, but has only minor effect on uveal blood flow in the cat. These observations agree well with the effects of sympathetic nerve stimulation, which in cats causes an uveal vasoconstriction that is completely abolished by α-adrenoreceptor blockade. In rabbits, the uveal vasoconstriction is resistant to α-adrenoreceptor blockade at high frequencies. The contribution of different neurotransmitters to the uveal vasodilatation caused by facial nerve stimulation seems to differ as well. In cats, the effect is almost abolished by muscarinic blockade combined with inhibition of nitric oxide synthase (NOS), indicating that nitric oxide and acetylcholine are the major transmitters. NO-inhibition and muscarinic blockade have only minor effects on the parasympathetic vasodilatation in the rabbit, however, suggesting that a peptide(s) can be the main mediator(s). In agreement with this, VIP, PHI and PACAP-27 and PACAP-38 are potent vasodilators in the rabbit choroid, but have no effect on uveal blood flows in the cat. The potency of PACAP-27 and PACAP-38 is about 100 times higher than that of VIP and PHI, indicating that selective PAC1 receptors may be involved. In humans, PACAP has been shown to increase blood flow velocity in the ophthalmic artery, indicating choroidal vasodilatation.

    Receptors for VIP/PACAP are present on the ciliary epithelium from several species, and VIP and PACAP-27 stimulates aqueous humour flow in monkeys.

    The significance of the various neuropeptides for the regulation ocular blood flow seems to vary considerably between species and the effects of neuropeptides on ocular circulation in humans is largely unknown.

  • 134.
    Nilsson, Siv
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Alm, Albert
    Division of Ophthalmology, Department of Neurosciences, University Hospital, University of Uppsala.
    Determination of Ocular Blood Flows with the Microsphere Method2012In: Ocular Blood Flow / [ed] Leopold Schmetterer, Jeffrey Kiel, Berlin Heidelberg: Springer-Verlag , 2012, p. 25-47Chapter in book (Refereed)
    Abstract [en]

    Adequate blood supply to the eye is an important prerequisite for normal visual function. Over the past 40 years our knowledge of ocular blood flow regulation has improved significantly. This lavishly illustrated textbook provides a comprehensive overview of the current knowledge of ocular blood flow by:Evaluating the wide array of methods for measuring ocular blood flow Offering the reader an evidence-based summary on the physiological and pharmacological properties of ocular blood flow regulation Demonstrating the ocular blood flow abnormalities in different vascular diseases.This reader-friendly and well-structured book will enhance the understanding of all who are interested in learning more about ocular blood flow in health and disease

  • 135.
    Nilsson, Ulrika K.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lysophosphatidic acid: Physiological effects and structure-activity relationships2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lipids havepreviously been considered primarily as building blocks of the cell membrane, but are now also recognized as important cell signaling molecules. Lysophosphatidic acid (LPA) is a glycerophospholipid consisting of a phosphate head group, a linker region, and a lipophilic tail. LPA has earlier been shown to exert a diversity of cellular effects such as aggregation, apoptosis, contraction, migration, and proliferation. The effects of LPA are elicited by activation of its cognate G protein-coupled receptors LPA1, LPA2, and LPA3. In the present study we have used cultures of human smooth muscle cells (SMCs) and erythroleukemia cells (HEL), and isolated human platelets to characterize physiological effects of LPA compared with adrenaline and noradrenaline as well as structure-activity relationships of LPA. SMCs were isolated from biopsies of human myometrium obtained at cesarean sections. We show that cultured myometrial SMCs express multiple LPA and α2-adrenergic receptor subtypes. Treatment of SMCs with LPA and noradrenaline resulted in increases in proliferation. However, LPA elicits a much more pronounced stimulatory effect than noradrenaline. The ability to increase calcium might be one explanation why LPA is more effective. Further studies indicated that several pathways mediate the growth stimulatory effect of LPA where transactivation of epidermal growth factor receptors through matrix metalloproteinases as well as calcium/calmodulin-dependent protein kinases appears to be important. LPA enantiomers and LPA analogues were synthesized and characterized due to their capacity to increase calcium in HEL cells. Our study is the first to show that both natural (R) and unnatural (S) LPA enantiomers are capable of stimulating cells, suggesting LPA receptors are not stereoselective. Moreover, we have synthesized a LPA analogue with higher maximal effect than LPA by reducing the hydrocarbon chain length. In platelets we demonstrated that LPA is a weak calciumelevating compound which failed to stimulate aggregation. However, in combination with adrenaline, another weak platelet agonist, a complete aggregatory response was obtained in blood from some healthy individuals. These results are important since platelet activation is a key step in distinguishing normal from pathological hemostasis. Since LPA is present at high concentrations in atherosclerotic lesions, the synergistic effect of LPA and adrenaline might be a new risk factor for arterial thrombosis.

    List of papers
    1. Different proliferative responses of Gi/o-protein-coupled receptors in human myometrial smooth muscle cells: a possible role of calcium
    Open this publication in new window or tab >>Different proliferative responses of Gi/o-protein-coupled receptors in human myometrial smooth muscle cells: a possible role of calcium
    1998 (English)In: Journal of Molecular Neuroscience, ISSN 0895-8696, Vol. 11, no 1, p. 11-21Article in journal (Refereed) Published
    Abstract [en]

    The majority of studies investigating the proliferative effect of Gi/o-protein-coupled receptor agonists are performed in recombinant receptor systems or cell lines. In these systems the relative stoichiometry of receptors compared to other cell components might be changed, which may lead to anomalies in cellular responses in contrast to natural occurring systems. In the present study, we have used primary cultures of smooth muscle cells (SMCs) isolated from human myometrium to characterize the proliferative effects of agonists binding to two different G protein-coupled receptors. Treatment of quiescent SMCs with lysophosphatidic acid (LPA) and noradrenaline resulted in significant increases in [3H]thymidine incorporation. However, LPA was almost four times more effective than noradrenaline in this respect. The proliferative effects of the agonists could be completely blocked by pertussis toxin, indicating that the response are mediated through Gi/o-proteins. The selective α2-adrenergic receptor (α2-AR) antagonist yohimbine dose-dependently reduced the effect of noradrenaline suggesting that the proliferative response was mediated through α2-ARs. The proliferative effects induced by LPA and noradrenaline was markedly reduced in SMCs treated with the tyrosine kinase inhibitor genistein and the cAMP elevating compound forskolin. However, LPA but not noradrenaline induced rapid rises in the cytosolic free Ca2+ concentration [Ca2+]i. The ability to increase Ca2+ might be one explanation why LPA produce a more pronounced proliferative response than noradrenaline in primary cultures of human myometrial SMCs.

    Keywords
    Uterus, smooth muscle cells, G protein-coupled receptors, DNA synthesis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13736 (URN)10.1385/JMN:11:1:11 (DOI)
    Available from: 2006-01-17 Created: 2006-01-17 Last updated: 2009-08-20
    2. Inhibition of Ca2 +/calmodulin-dependent protein kinase or epidermal growth factor receptor tyrosine kinase abolishes lysophosphatidic acid-mediated DNA-synthesis in human myometrial smooth muscle cells
    Open this publication in new window or tab >>Inhibition of Ca2 +/calmodulin-dependent protein kinase or epidermal growth factor receptor tyrosine kinase abolishes lysophosphatidic acid-mediated DNA-synthesis in human myometrial smooth muscle cells
    2003 (English)In: Cell Biology International, ISSN 1065-6995, Vol. 27, no 4, p. 341-347Article in journal (Refereed) Published
    Abstract [en]

    Human myometrial smooth muscle cells (SMCs) were used to evaluate the proliferative activity of lysophosphatidic acid (LPA). This study specifically focuses on the role of Ca2+/calmodulin-dependent protein (CaM) kinase and epidermal growth factor (EGF) receptor tyrosine kinase. Myometrial SMCs were cultured from biopsies taken at Cesarean sections. The expression of LPA receptors was determined by reverse transcriptase polymerase chain reaction (RT-PCR), and DNA-synthesis was measured by [3H]thymidine incorporation. LPA1, LPA2, and LPA3receptor subtypes were detected in the SMCs using RT-PCR. KN-62, an inhibitor of CaM kinase, and Tyrphostin AG 1478, an inhibitor of EGF receptor tyrosine kinase, dose-dependently decreased LPA-stimulated [3H]thymidine incorporation. Furthermore, BB-3103, an inhibitor of matrix metalloproteinases (MMPs), also reduced DNA-synthesis induced by LPA in these cells. The results show, for the first time, that human myometrial SMCs express all three known LPA receptor subtypes. Growth stimulatory effects of LPA on myometrial SMCs seems to be mediated by several pathways, where transactivation of EGF receptors through MMPs appears to be of importance. Furthermore, CaM kinase activity may be critical for LPA signaling since inhibition of CaM kinase totally abolish the proliferative effect of LPA.

    Keywords
    Calcium, Calmodulin, DNA-synthesis, Epidermal growth factor, Lysophosphatidic acid, Smooth muscle cells
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13737 (URN)10.1016/S1065-6995(02)00352-9 (DOI)
    Available from: 2006-01-17 Created: 2006-01-17
    3. Synergistic activation of human platelets by adrenaline and lysophosphatidic acid
    Open this publication in new window or tab >>Synergistic activation of human platelets by adrenaline and lysophosphatidic acid
    2002 (English)In: Haematologica, ISSN 0390-6078, Vol. 87, no 7, p. 730-739Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Platelet reactivity is regulated by various important bioactive and physiologic substances. The objective of this study was to characterize lysophosphatidic acid (LPA)-triggered responses in human platelets. In addition, the effect of LPA was compared with that of other activators and possible synergistic interactions were evaluated.

    DESIGN AND METHODS: LPA-triggered cytosolic Ca(2+) responses were measured using fura-2-loaded platelets in a spectrofluorometer. Furthermore, platelet aggregation and secretion were analyzed in a lumi-aggregometer and protein tyrosine phosphorylation was detected with the Western blot technique.

    RESULTS: LPA dose-dependently increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in platelets. This response involved both influx of extracellular Ca(2+) and release of Ca(2+) from intracellular stores. However, in comparison with other platelet agonists, i.e. thrombin and adenosine 5'-diphosphate (ADP), LPA was a very weak Ca(2+)-elevating agent. Furthermore, we observed that the LPA-induced rise in [Ca(2+)](i) was markedly suppressed by cyclic nucleotide-elevating agents. In functional studies, LPA failed to stimulate platelet aggregation and secretion. However, in combination with adrenaline, another weak platelet agonist, LPA could induce an irreversible and complete aggregatory response. There was an individual variation in aggregatory response and tyrosine phosphorylation when LPA and adrenaline were combined. These agents induced a powerful response on platelets from some individuals, but had a weak or no effect on others.

    INTERPRETATION AND CONCLUSIONS: The present study shows, for the first time, that isolated platelets from some healthy blood donors respond synergistically to a combination of LPA and adrenaline. Platelet activation is a key step in distinguishing normal hemostasis from pathologic hemostasis. Increased knowledge about this mechanism might help to predict individual responses and provide new insights into molecular mechanisms responsible for pathologic thrombosis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13738 (URN)
    Available from: 2006-01-17 Created: 2006-01-17 Last updated: 2009-05-28
    4. Lack of stereospecificity in lysophosphatidic acid enantiomerinduced calcium mobilization in human erythroleukemia cells
    Open this publication in new window or tab >>Lack of stereospecificity in lysophosphatidic acid enantiomerinduced calcium mobilization in human erythroleukemia cells
    Show others...
    2003 (English)In: Lipids, ISSN 0024-4201, Vol. 38, no 10, p. 1057-1064Article in journal (Refereed) Published
    Abstract [en]

    Lysophosphatidic acid (LPA) is a lipid mediator that, among several other cellular responses, can stimulate cells to mobilize calcium (Ca2+). LPA is known to activate at least three different subtypes of G protein-coupled receptors. These receptors can then stimulate different kinds of G proteins. In the present study, LPA and LPA analogs were synthesized from (R)- and (S)-glycidol and used to characterize the ability to stimulate Ca2+ mobilization. The cytosolic Ca2+ concentration ([Ca2+]i) was measured in fura-2-acetoxymethylester-loaded human erythroleukemia (HEL) cells. Furthermore, a reverse transcriptase polymerase chain reaction was used to characterize LPA receptor subtypes expressed in HEL cells. The results show that HEL cells mainly express LPA1 and LPA2, although LPA3 might possibly be expressed as well. Moreover, LPA and its analogs concentration-dependently increased [Ca2+]i in HEL cells. The response involved both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores. This is the first time the unnatural (S)-enantiomer of LPA, (S)-3-O-oleoyl-1-O-phosphoryl-glycerol, has been synthesized and studied according to its ability to activate cells. The results indicate that this group of receptors does not discriminate between (R)- and (S)-enantiomers of LPA and its analogs. When comparing ether analogs having different hydrocarbon chain lengths, the tetradecyl analog (14 carbons) was found to be the most effective in increasing [Ca2+]i. Pertussis toxin treatment of the HEL cells resulted in an even more efficient Ca2+ mobilization stimulated by LPA and its analogs. Furthermore, at repeated incubation with the same ligand no further increase in [Ca2+]i was obtained. When combining LPA with the ether analogs no suppression of the new Ca2+ signal occurred. All these findings may be of significance in the process of searching for specific agonists and antagonists of the LPA receptor subtypes.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-13739 (URN)
    Available from: 2006-01-17 Created: 2006-01-17
  • 136.
    Nilsson, Ulrika K.
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G. G.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Ekeroth, Johan
    Linköping University, Department of Physics, Chemistry and Biology.
    Hallin, Elisabeth C.
    Linköping University, Department of Clinical and Experimental Medicine, Cellbiology. Linköping University, Faculty of Health Sciences.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Lindberg, Jan
    Linköping University, Department of Physics, Chemistry and Biology.
    Svensson, Samuel P.S.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Lack of stereospecificity in lysophosphatidic acid enantiomerinduced calcium mobilization in human erythroleukemia cells2003In: Lipids, ISSN 0024-4201, Vol. 38, no 10, p. 1057-1064Article in journal (Refereed)
    Abstract [en]

    Lysophosphatidic acid (LPA) is a lipid mediator that, among several other cellular responses, can stimulate cells to mobilize calcium (Ca2+). LPA is known to activate at least three different subtypes of G protein-coupled receptors. These receptors can then stimulate different kinds of G proteins. In the present study, LPA and LPA analogs were synthesized from (R)- and (S)-glycidol and used to characterize the ability to stimulate Ca2+ mobilization. The cytosolic Ca2+ concentration ([Ca2+]i) was measured in fura-2-acetoxymethylester-loaded human erythroleukemia (HEL) cells. Furthermore, a reverse transcriptase polymerase chain reaction was used to characterize LPA receptor subtypes expressed in HEL cells. The results show that HEL cells mainly express LPA1 and LPA2, although LPA3 might possibly be expressed as well. Moreover, LPA and its analogs concentration-dependently increased [Ca2+]i in HEL cells. The response involved both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores. This is the first time the unnatural (S)-enantiomer of LPA, (S)-3-O-oleoyl-1-O-phosphoryl-glycerol, has been synthesized and studied according to its ability to activate cells. The results indicate that this group of receptors does not discriminate between (R)- and (S)-enantiomers of LPA and its analogs. When comparing ether analogs having different hydrocarbon chain lengths, the tetradecyl analog (14 carbons) was found to be the most effective in increasing [Ca2+]i. Pertussis toxin treatment of the HEL cells resulted in an even more efficient Ca2+ mobilization stimulated by LPA and its analogs. Furthermore, at repeated incubation with the same ligand no further increase in [Ca2+]i was obtained. When combining LPA with the ether analogs no suppression of the new Ca2+ signal occurred. All these findings may be of significance in the process of searching for specific agonists and antagonists of the LPA receptor subtypes.

  • 137.
    Nilsson, Ulrika K.
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Berg, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Gynecology and Obstetrics in Linköping.
    Svensson, Samuel P.S.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Different proliferative responses of Gi/o-protein-coupled receptors in human myometrial smooth muscle cells: a possible role of calcium1998In: Journal of Molecular Neuroscience, ISSN 0895-8696, Vol. 11, no 1, p. 11-21Article in journal (Refereed)
    Abstract [en]

    The majority of studies investigating the proliferative effect of Gi/o-protein-coupled receptor agonists are performed in recombinant receptor systems or cell lines. In these systems the relative stoichiometry of receptors compared to other cell components might be changed, which may lead to anomalies in cellular responses in contrast to natural occurring systems. In the present study, we have used primary cultures of smooth muscle cells (SMCs) isolated from human myometrium to characterize the proliferative effects of agonists binding to two different G protein-coupled receptors. Treatment of quiescent SMCs with lysophosphatidic acid (LPA) and noradrenaline resulted in significant increases in [3H]thymidine incorporation. However, LPA was almost four times more effective than noradrenaline in this respect. The proliferative effects of the agonists could be completely blocked by pertussis toxin, indicating that the response are mediated through Gi/o-proteins. The selective α2-adrenergic receptor (α2-AR) antagonist yohimbine dose-dependently reduced the effect of noradrenaline suggesting that the proliferative response was mediated through α2-ARs. The proliferative effects induced by LPA and noradrenaline was markedly reduced in SMCs treated with the tyrosine kinase inhibitor genistein and the cAMP elevating compound forskolin. However, LPA but not noradrenaline induced rapid rises in the cytosolic free Ca2+ concentration [Ca2+]i. The ability to increase Ca2+ might be one explanation why LPA produce a more pronounced proliferative response than noradrenaline in primary cultures of human myometrial SMCs.

  • 138.
    Nilsson, Ulrika K.
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Svensson, Samuel P.S.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Synergistic activation of human platelets by adrenaline and lysophosphatidic acid2002In: Haematologica, ISSN 0390-6078, Vol. 87, no 7, p. 730-739Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Platelet reactivity is regulated by various important bioactive and physiologic substances. The objective of this study was to characterize lysophosphatidic acid (LPA)-triggered responses in human platelets. In addition, the effect of LPA was compared with that of other activators and possible synergistic interactions were evaluated.

    DESIGN AND METHODS: LPA-triggered cytosolic Ca(2+) responses were measured using fura-2-loaded platelets in a spectrofluorometer. Furthermore, platelet aggregation and secretion were analyzed in a lumi-aggregometer and protein tyrosine phosphorylation was detected with the Western blot technique.

    RESULTS: LPA dose-dependently increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in platelets. This response involved both influx of extracellular Ca(2+) and release of Ca(2+) from intracellular stores. However, in comparison with other platelet agonists, i.e. thrombin and adenosine 5'-diphosphate (ADP), LPA was a very weak Ca(2+)-elevating agent. Furthermore, we observed that the LPA-induced rise in [Ca(2+)](i) was markedly suppressed by cyclic nucleotide-elevating agents. In functional studies, LPA failed to stimulate platelet aggregation and secretion. However, in combination with adrenaline, another weak platelet agonist, LPA could induce an irreversible and complete aggregatory response. There was an individual variation in aggregatory response and tyrosine phosphorylation when LPA and adrenaline were combined. These agents induced a powerful response on platelets from some individuals, but had a weak or no effect on others.

    INTERPRETATION AND CONCLUSIONS: The present study shows, for the first time, that isolated platelets from some healthy blood donors respond synergistically to a combination of LPA and adrenaline. Platelet activation is a key step in distinguishing normal hemostasis from pathologic hemostasis. Increased knowledge about this mechanism might help to predict individual responses and provide new insights into molecular mechanisms responsible for pathologic thrombosis.

  • 139.
    Nilsson, Ulrika K.
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Svensson, Samuel P.S.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Inhibition of Ca2 +/calmodulin-dependent protein kinase or epidermal growth factor receptor tyrosine kinase abolishes lysophosphatidic acid-mediated DNA-synthesis in human myometrial smooth muscle cells2003In: Cell Biology International, ISSN 1065-6995, Vol. 27, no 4, p. 341-347Article in journal (Refereed)
    Abstract [en]

    Human myometrial smooth muscle cells (SMCs) were used to evaluate the proliferative activity of lysophosphatidic acid (LPA). This study specifically focuses on the role of Ca2+/calmodulin-dependent protein (CaM) kinase and epidermal growth factor (EGF) receptor tyrosine kinase. Myometrial SMCs were cultured from biopsies taken at Cesarean sections. The expression of LPA receptors was determined by reverse transcriptase polymerase chain reaction (RT-PCR), and DNA-synthesis was measured by [3H]thymidine incorporation. LPA1, LPA2, and LPA3receptor subtypes were detected in the SMCs using RT-PCR. KN-62, an inhibitor of CaM kinase, and Tyrphostin AG 1478, an inhibitor of EGF receptor tyrosine kinase, dose-dependently decreased LPA-stimulated [3H]thymidine incorporation. Furthermore, BB-3103, an inhibitor of matrix metalloproteinases (MMPs), also reduced DNA-synthesis induced by LPA in these cells. The results show, for the first time, that human myometrial SMCs express all three known LPA receptor subtypes. Growth stimulatory effects of LPA on myometrial SMCs seems to be mediated by several pathways, where transactivation of EGF receptors through MMPs appears to be of importance. Furthermore, CaM kinase activity may be critical for LPA signaling since inhibition of CaM kinase totally abolish the proliferative effect of LPA.

  • 140. Nimeri, G
    et al.
    Majeed, Meytham
    Linköping University, Faculty of Arts and Sciences. Linköping University, Department of health and environment.
    Elwing, H
    Öhman, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Infectious Diseases . Östergötlands Läns Landsting, Centre for Medicine, Department of Infectious Diseases in Östergötland.
    Wetterö, Jonas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Rheumatology .
    Bengtsson, Torbjörn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Oxygen radical production in neutrophils interacting with platelets and surface-immobilized plasma proteins: role of tyrosine phosphorylation2003In: Journal of Biomedical Materials Research, ISSN 0021-9304, E-ISSN 1097-4636, Vol. 67A, no 2, p. 439-447Article in journal (Refereed)
    Abstract [en]

    The interaction between neutrophil granulocytes and platelets is considered to play an important role in the inflammatory process induced by an implanted foreign material. However, the cellular mechanisms involved remain incompletely understood. We used a luminol-dependent chemiluminescence (CL) technique to analyze the generation of reactive oxygen species (ROS) in human neutrophils interacting with different plasma protein-coated surfaces in the presence or absence of unstimulated or stimulated platelets. The role of tyrosine phosphorylation in the regulation of NADPH oxidase activity was evaluated with quantitative fluorescence microscopy and the specific tyrosine kinase inhibitor genistein. We found that the ROS-production is 2 to 3 times higher in neutrophils on immunoglobulin G (IgG)coated surfaces than in cells interacting with albumin- or fibrinogen-coated surfaces. Incubation with superoxide dismutase and catalase revealed that about 45% of the ROS was released extracellularly on IgG surfaces whereas corresponding values were 90% and 85% in neutrophils interacting with albumin and fibrinogen, respectively. The presence of platelets markedly increased the extracellular generation of ROS, mainly in neutrophils. interacting with IgG- or fibrinogen-coated surfaces whereas the intracellular production was only modestly affected. Quantitative fluorescence microscopy of neutrophils stained with FITC-conjugated anti-phosphotyrosine antibodies showed a correlation between tyrosine phosphorylation, cell spreading, and ROS production. Platelets markedly amplified the anti-phosphotyrosine staining on both fibrinogen- and IgG-coated surfaces whereas the low level of tyrosine phosphorylation in neutrophils on albumin-coated surfaces was not further elevated by platelets. Furthermore, the tyrosine kinase inhibitor genistein inhibited both extra- and intracellular ROS production in neutrophils regardless of the presence of platelets. We demonstrate that plasma protein coating and the presence of platelets are crucial for the inflammatory response of adhering neutrophils and that the oxidative response correlates with the extent of tyrosine phosphorylation of proteins in focal contacts. (C) 2003 Wiley Periodicals, Inc.

  • 141.
    Nylander, Martina
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    The thrombin receptors PAR1 and PAR4 and their relative role in platelet activation2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Many blood cell mechanisms in the human body are working all the time to maintain haemostasis in the blood vessels. Once a wound arises platelets are alerted via different substances to cover the wound and prevent loss of blood. Most of the times these mechanisms do stop the blood, and further heal the wound. During other circumstances the platelet-covering continues to form a thrombus, preventing the blood to flow and instead causes myocardial infarction or stroke. There are several risk factors triggering development of circulatory diseases such as obesity, lack of exercise, smoking, infection and stress.

    This thesis describes the interaction between the two platelet thrombin receptors PAR1 and PAR4, together with the interaction of the oral pathogen Porphyromonas gingivalis (with thrombin-like gingipains), and the cross talk with the stress hormone epinephrine and its α2A adrenergic receptor. Until now PAR1 is thought to be the most important thrombin receptor due to its high affinity for thrombin. From a phylogenetical and patophysiological point of view there must be a reason why platelets express two different thrombin receptors. Today PAR4 is considered less important, but this thesis implies that PAR4 plays an important role in platelet signaling and haemostasis.

    The results show that bacteria pre-stimulated platelets, followed by epinephrine gives a strong and full aggregation and calcium mobilization, in both aspirinated and non-aspirinated human platelets. The amount of bacteria does not itself, or epinephrine alone give aggregation or calcium mobilization. This mechanism is dependent on both Rgp type gingipain released from P. gingivalis, and PARs in an interaction with the α2A adrenergic receptor.

    Further, results reveal that PAR4 interacts and cross talks with the platelet α2A-adrenergic receptor in aspirinated platelets. Neither of the two platelet purinergic P2Y-receptors (P2Y12 and P2Y1) contribute to this action, but the purinergic P2X1 does. In aggregation studies a low dose of PAR4 activating peptide (AP), but not PAR1-AP, followed by epinephrine results in a strong aggregation and in a calcium mobilization. ATP secretion measurements did reveal that ATP was released during epinephrine stimulation, which indicate that ATP and P2X1 have a key role in this event. By blocking P2X1 both aggregation and calcium mobilization were abolished, but not by blocking P2Y12 and P2Y1. Inhibition of PI3-kinase, both epinephrine-induced calcium mobilization and aggregation were significant reduced. In non-aspirinated platelets PAR1 synergizes with the α2A adrenergic receptor and P2X1.

    In conclusion, this thesis suggests that PAR4 plays an intriguing and important role in platelets with inactived cyclooxygenase 1.  The results described in this thesis contribute to an increased knowledge of the platelet thrombin receptors.

    List of papers
    1. The periodontal pathogen Porphyromonas gingivalis sensitises human blood platelets to epinephrine
    Open this publication in new window or tab >>The periodontal pathogen Porphyromonas gingivalis sensitises human blood platelets to epinephrine
    2008 (English)In: Platelets, ISSN 1369-1635, Vol. 19, no 5, p. 352-358Article in journal (Refereed) Published
    Abstract [en]

    Recent studies indicate connections between periodontitis and atherothrombosis, and the periodontal pathogen Porphyromonas gingivalis has been found within atherosclerotic lesions. P. gingivalis-derived proteases, designated gingipains activate human platelets, probably through a "thrombin-like" activity on protease-activated receptors (PARs). However, the potential interplay between P. gingivalis and other physiological platelet activators has not been investigated. The aim of this study was to elucidate consequences and mechanisms in the interaction between P. gingivalis and the stress hormone epinephrine. By measuring changes in light transmission through platelet suspensions, we found that P. gingivalis provoked aggregation, whereas epinephrine alone never had any effect. Intriguingly, pre-treatment of platelets with a low, sub-threshold number of P. gingivalis (i.e. a density that did not directly provoke platelet aggregation) resulted in a marked aggregation response when epinephrine was added. This synergistic action was not inhibited by the cyclooxygenas inhibitor aspirin. Furthermore, fura-2-measurements revealed that epinephrine caused an intracellular Ca(2+) mobilization in P. gingivalis pre-treated platelets, whereas epinephrine alone had no effect. Inhibition of the arg-specific gingipains, but not the lys-specific gingipains, abolished the aggregation and the Ca(2+) response provoked by epinephrine. Similar results were achieved by separate blockage of platelet alpha(2)-adrenergic receptors and PARs. In conclusion, the present study shows that a sub-threshold number of P. gingivalis sensitizes platelets to epinephrine. We suggest that P. gingivalis-derived arg-specific gingipains activates a small number of PARs on the surface of the platelets. This leads to an unexpected Ca(2+) mobilization and a marked aggregation response when epinephrine subsequently binds to the alpha(2)-adrenergic receptor. The present results are consistent with a direct connection between periodontitis and stress, and describe a novel mechanism that may contribute to pathological platelet activation.

    Place, publisher, year, edition, pages
    Taylor & Francis, 2008
    Keywords
    Atherosclerosis, growth factors, infection, inflammation, lipoproteins
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20725 (URN)10.1080/09537100802056102 (DOI)18791941 (PubMedID)
    Available from: 2009-09-18 Created: 2009-09-18 Last updated: 2011-10-14
    2. The ATP-gated P2X1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine
    Open this publication in new window or tab >>The ATP-gated P2X1 receptor plays a pivotal role in activation of aspirin-treated platelets by thrombin and epinephrine
    Show others...
    2008 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 283, no 27, p. 18493-18504Article in journal (Refereed) Published
    Abstract [en]

    Human platelets express protease-activated receptor 1 (PAR1) and PAR4 but limited data indicate for differences in signal transduction. We studied the involvement of PAR1 and PAR4 in the cross-talk between thrombin and epinephrine. The results show that epinephrine acted via alpha(2A)-adrenergic receptors to provoke aggregation, secretion, and Ca(2+) mobilization in aspirin-treated platelets pre-stimulated with subthreshold concentrations of thrombin. Incubating platelets with antibodies against PAR4 or the PAR4-specific inhibitor pepducin P4pal-i1 abolished the aggregation. Furthermore, platelets pre-exposed to the PAR4-activating peptide AYPGKF, but not to the PAR1-activating peptide SFLLRN, were aggregated by epinephrine, whereas both AYPGKF and SFLLRN synergized with epinephrine in the absence of aspirin. The roles of released ATP and ADP were elucidated by using antagonists of the purinergic receptors P2X(1), P2Y(1), and P2Y(12) (i.e. NF449, MRS2159, MRS2179, and cangrelor). Intriguingly, ATP, but not ADP, was required for the epinephrine/thrombin-induced aggregation. In Western blot analysis, a low concentration of AYPGKF, but not SFLLRN, stimulated phosphorylation of Akt on serine 473. Moreover, the phosphatidyl inositide 3-kinase inhibitor LY294002 antagonized the effect of epinephrine combined with thrombin or AYPGKF. Thus, in aspirin-treated platelets, PAR4, but not PAR1, interacts synergistically with alpha(2A)-adrenergic receptors, and the PI3-kinase/Akt pathway is involved in this cross-talk. Furthermore, in PAR4-pretreated platelets, epinephrine caused dense granule secretion, and subsequent signaling from the ATP-gated P2X(1)-receptor and the alpha(2A)-adrenergic receptor induced aggregation. These results suggest a new mechanism that has ATP as a key element and circumvents the action of aspirin on epinephrine-facilitated PAR4-mediated platelet activation.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20726 (URN)10.1074/jbc.M800358200 (DOI)18480058 (PubMedID)
    Available from: 2009-09-18 Created: 2009-09-18 Last updated: 2017-12-13Bibliographically approved
  • 142.
    Nylander, Martina
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Fälker, Knut
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Release of ADP or PAR4 Activation is Required to Sustain Thrombin-induced Platelet AggregationManuscript (preprint) (Other academic)
    Abstract [en]

    Thrombin activates human platelets through cleavage of two G-protein-coupled proteaseactivatedreceptors (PARs) denoted PAR1 and PAR4. The aim of this study was to investigatedifferences in PAR1 and PAR4 signaling regarding formation and stability of plateletaggregates. We show that weak PAR1-mediated aggregation is reversible, whereas PAR4-mediated aggregation, weak or strong, is always sustained. PAR1-induced plateletaggregation is decreased and more reversible in the presence of the P2Y12 antagonistcangrelor. However, the effects by cangrelor can be concentration-dependently reversed byconcomitant PAR4 activation in a PI3-kinase-dependent manner. In contrast; in PAR4-APstimulated platelets, aggregation is reduced by cangrelor or inhibition of PI3-kinase byLY294002 but remains irreversible. However, a combined inhibition of PI3-K and P2Y12results in reduced and reversible aggregation. In the light of recently published data on PAR1desensitization, we suggest that the physiological role of the differences between PAR1 andPAR4 activation on aggregate and clot stability could be to fine-tune the response tothrombin. A repeated or continuous very low thrombin generation will desensitize PAR1 andeven if small platelet aggregates are formed they will dissolve, preventing inappropriatethrombus formation. At higher concentrations of thrombin, PAR4 will become activatedabrogating desensitization of PAR1 and enforcing stability of platelet aggregates.

  • 143.
    Nylander, Martina
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Bengtsson, Torbjörn
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Grenegård, Magnus
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    The periodontal pathogen Porphyromonas gingivalis sensitises human blood platelets to epinephrine2008In: Platelets, ISSN 1369-1635, Vol. 19, no 5, p. 352-358Article in journal (Refereed)
    Abstract [en]

    Recent studies indicate connections between periodontitis and atherothrombosis, and the periodontal pathogen Porphyromonas gingivalis has been found within atherosclerotic lesions. P. gingivalis-derived proteases, designated gingipains activate human platelets, probably through a "thrombin-like" activity on protease-activated receptors (PARs). However, the potential interplay between P. gingivalis and other physiological platelet activators has not been investigated. The aim of this study was to elucidate consequences and mechanisms in the interaction between P. gingivalis and the stress hormone epinephrine. By measuring changes in light transmission through platelet suspensions, we found that P. gingivalis provoked aggregation, whereas epinephrine alone never had any effect. Intriguingly, pre-treatment of platelets with a low, sub-threshold number of P. gingivalis (i.e. a density that did not directly provoke platelet aggregation) resulted in a marked aggregation response when epinephrine was added. This synergistic action was not inhibited by the cyclooxygenas inhibitor aspirin. Furthermore, fura-2-measurements revealed that epinephrine caused an intracellular Ca(2+) mobilization in P. gingivalis pre-treated platelets, whereas epinephrine alone had no effect. Inhibition of the arg-specific gingipains, but not the lys-specific gingipains, abolished the aggregation and the Ca(2+) response provoked by epinephrine. Similar results were achieved by separate blockage of platelet alpha(2)-adrenergic receptors and PARs. In conclusion, the present study shows that a sub-threshold number of P. gingivalis sensitizes platelets to epinephrine. We suggest that P. gingivalis-derived arg-specific gingipains activates a small number of PARs on the surface of the platelets. This leads to an unexpected Ca(2+) mobilization and a marked aggregation response when epinephrine subsequently binds to the alpha(2)-adrenergic receptor. The present results are consistent with a direct connection between periodontitis and stress, and describe a novel mechanism that may contribute to pathological platelet activation.

  • 144.
    Nylander, Martina
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lofgren, E
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Larsson, A
    Uppsala University.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    PAI-1 secretion, re-synthesizing and the role of thrombin receptors in platelets in JOURNAL OF THROMBOSIS AND HAEMOSTASIS, vol 9, issue SI, pp 70-702011In: JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Wiley-Blackwell , 2011, Vol. 9, no SI, p. 70-70Conference paper (Refereed)
    Abstract [en]

    n/a

  • 145.
    Nylander, Martina
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Ramström, Sofia
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Åklint, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Larsson, Anders
    Department of Medical Sciences, University Hospital, Uppsala, Sweden.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    The role of thrombin receptors PAR1 and PAR4 for PAI-1 storage, synthesis and secretion by human platelets2012In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 129, no 4, p. E51-E58Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Arterial thrombi contain more platelets than venous thrombi and are more resistant to fibrinolysis. This resistance could partly be due to plasminogen activator inhibitor 1 (PAI-1) secreted by platelets. The aim of this study was to elucidate differences between thrombin receptors protease-activated receptor (PAR) 1 and 4 and platelet storage, secretion and synthesis of platelet PAI-1, as compared to other platelet α-granule proteins such as VEGF and endostatin.

    MATERIALS AND METHODS:

    Human isolated platelets were incubated with thrombin (0.5U/ml), PAR1-activating peptide (AP) (0.4-30μM) or PAR4-AP (1.5-300μM) for up to 24hours. ELISA, western blot and fluorescence microscopy were used to measure secretion, contents and localization of PAI-1, VEGF and endostatin.

    RESULTS:

    Our results show that PAI-1 and VEGF might be co-localized and that endostatin does not co-localize with either PAI-1 or VEGF. PAI-1 and VEGF show a similar secretion pattern, being more sensitive to low grade PAR1 activation, but secretion was also observed with higher concentrations of PAR4-APs. PAI-1 is secreted in an active form. PAI-1 mRNA was found in platelets, and elevated levels of PAI-1 were detected after 24hours incubation of platelets.

    CONCLUSIONS:

    PAI-1 and VEGF, but not endostatin, might be stored in the same α-granule in human platelets. PAI-1 and VEGF also show a similar secretion pattern, being more sensitive to PAR1 than to PAR4 activation, but the secretion is not exclusively selective. Our results also show that platelet PAI-1 is increased if incubated for 24hours, both with addition of PAR1-activating peptide and without activation, which could indicate de novo synthesis.

  • 146.
    Ohlsson, S M
    et al.
    Lund University, Sweden .
    Pettersson, A
    Lund University, Sweden .
    Ohlsson, S
    Lund University, Sweden .
    Selga, D
    Lund University, Sweden .
    Bengtsson, A A
    Lund University, Sweden .
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Nephrology UHL.
    Hellmark, T
    Lund University, Sweden .
    Phagocytosis of apoptotic cells by macrophages in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis2012In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 170, no 1, p. 47-56Article in journal (Refereed)
    Abstract [en]

    Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is not known why ANCA develop, but it has been shown that they participate in pathogenesis by activating polymorphonuclear neutrophils (PMNs). In this study we hypothesize that dysregulation of phagocytosis in AAV leads to the accumulation of apoptotic neutrophils seen in association with blood vessels in AAV. These cells progress into secondary necrosis, contributing to tissue damage and autoantibody formation. Peripheral blood cells were counted, and phagocytosis was investigated using monocyte-derived macrophages (M circle divide) and PMNs from healthy blood donors (HBD), AAV patients and systemic lupus erythematosus (SLE) patients. Furthermore, the effect of serum was assessed. Phagocytosis was measured using flow cytometry. The results showed no deviation in monocyte subpopulations for AAV patients compared to HBDs, although there was a decrease in lymphocyte and pDC (plasmacytoid dendritic cell) populations (4.2 X 106 cells/l versus 10.4 X 106 cells/l, P andlt; 0.001). The number of neutrophils was increased (6.0 X 109 cells/l versus 3.8 X 109 cells/l, P andlt; 0.001). There were no differences found in the ability of M circle divide s to engulf apoptotic cells, nor when comparing apoptotic PMNs to become engulfed. However, serum from AAV donors tended to decrease the phagocytosis ability of M circle divide s (36%) compared to serum from HBDs (43%). In conclusion, there is no intrinsic dysfunction in the M circle divide s or in the PMNs that have an effect on phagocytic activity, but ANCA may play a role by decreasing phagocytic ability.

  • 147.
    Pagano, G.
    et al.
    Italian National Cancer Institute, G. Pascale Foundation, Paediatric Oncology Research Centre, Mercogliano (AV), Italy, Istituto Nazionale Tumori, Fondazione G. Pascale, v. M. Semmola, I-80131 Naples, Italy.
    Youssoufian, H.
    Clinical Discovery, Bristol-Myers Squibb Company, Princeton, NJ, United States.
    Anak, S.S.
    Dept. of Paediat. Haematol./Oncolog., Istanbul Univ. School of Medicine, Istanbul, Turkey.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Calzone, R.
    Department of Genetics, Elena d'Aosta Hospital, Naples, Italy.
    Clarke, A.A.
    Department of Haematology, St. George's Hosp. Medical School, University of London, London, United Kingdom.
    Degan, P.
    Italian National Cancer Institute, Genoa, Italy.
    D'Ischia, M.
    Department of Organic Chemistry, Federico II Naples University, Naples, Italy, Department of Physiology, Valencia University, Valencia, Spain.
    Dunster, C.
    Division of Life Sciences, King's College, London, United Kingdom.
    Giudice, A.
    Italian National Cancer Institute, Genoa, Italy.
    Iaccarino, M.
    Italian National Cancer Institute, Genoa, Italy.
    Hirsch-Kauffmann, M.
    Kelly, F.J.
    Division of Life Sciences, King's College, London, United Kingdom.
    Lloret, A.
    Department of Organic Chemistry, Federico II Naples University, Naples, Italy, Department of Physiology, Valencia University, Valencia, Spain.
    Malorni, W.
    Italian Natl. Inst. of Hlth. (ISS), Rome, Italy.
    Manini, P.
    Department of Organic Chemistry, Federico II Naples University, Naples, Italy, Department of Physiology, Valencia University, Valencia, Spain.
    Masella, R.
    Italian Natl. Inst. of Hlth. (ISS), Rome, Italy.
    Nobili, B.
    Department of Paediatrics, 2nd Naples University, Naples, Italy.
    Pallardo, F.V.
    Pallardó, F.V., Department of Organic Chemistry, Federico II Naples University, Naples, Italy, Department of Physiology, Valencia University, Valencia, Spain.
    Schweiger, M.
    Department of Biochemistry, Free University Berlin, Berlin, Germany.
    Vuttariello, E.
    Italian National Cancer Institute, Genoa, Italy.
    Youssoufian, G.
    John Whiterspoon Middle School, Princeton, NJ, United States.
    Zatterale, A.
    Department of Genetics, Elena d'Aosta Hospital, Naples, Italy.
    Fanconi anaemia proteins: Major roles in cell protection against oxidative damage2003In: Bioessays, ISSN 0265-9247, E-ISSN 1521-1878, Vol. 25, no 6, p. 589-595Article, review/survey (Refereed)
    Abstract [en]

    Fanconi anaemia (FA) is a cancer-prone genetic disorder that is characterised by cytogenetic instability and redox abnormalities. Although rare subtypes of FA (B, D1 and D2) have been implicated in DNA repair through links with BRCA1 and BRCA2, such a role has yet to be demonstrated for gene products of the common subtypes. Instead, these products have been strongly implicated in xenobiotic metabolism and redox homeostasis through interactions of FANCC with cytochrome P-450 reductase and with glutathione S-transferase, and of FANCG with cytochrome P-450 2E1, as well as redox-dependent signalling through an interaction between FANCA and Akt kinase. We hypothesise that FA proteins act directly (via FANCC and FANCG) and indirectly (via FANCA, BRCA2 and FANCD2) with the machinery of cellular defence to modulate oxidative stress. The latter interactions may co-ordinate the link between the response to DNA damage and oxidative stress parameters (3, 6-12). © 2003 Wiley Periodicals, Inc.

  • 148.
    Persson, H.Lennart
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Respiratory Medicine.
    Kurz, Tino
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Eaton, John Wallace
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Radiation-induced cell death: Importance of lysosomal destabilization2005In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 389, no 3, p. 877-884Article in journal (Refereed)
    Abstract [en]

    The mechanisms involved in radiation-induced cellular injury and death remain incompletely understood. In addition to the direct formation of highly reactive hydroxyl radicals (HO.) by radiolysis of water, oxidative stress events in the cytoplasm due to formation of H2O2 may also be important. Since the major pool of low-mass redox-active intracellular iron seems to reside within lysosomes, arising from the continuous intralysosomal autophagocytotic degradation of ferruginous materials, formation of H2O2 inside and outside these organelles may cause lysosomal labilization with release to the cytosol of lytic enzymes and low-mass iron. If of limited magnitude, such release may induce 'reparative autophagocytosis', causing additional accumulation of redox-active iron within the lysosomal compartment. We have used radio-resistant histiocytic lymphoma (J774) cells to assess the importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury. We found that a 40 Gy radiation dose increased the 'loose' iron content of the (still viable) cells approx. 5-fold when assayed 24 h later. Cytochemical staining revealed that most redox-active iron was within the lysosomes. The increase of intralysosomal iron was associated with 'reparative autophagocytosis', and sensitized cells to Iysosomal rupture and consequent apoptotic/necrotic death following a second, much lower dose of radiation (20 Gy) 24 h after the first one. A high-molecular-mass derivative of desferrioxamine, which specifically localizes intralysosomally following endocytic uptake, added to the culture medium before either the first or the second dose of radiation, stabilized lysosomes and largely prevented cell death. These observations may provide a biological rationale for fractionated radiation. © 2005 Biochemical Society.

  • 149.
    Persson, Ingrid
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Pharmacology .
    Plant-Derived Substances and Cardiovascular Diseases: Effects of Flavonoids, Terpenes and Sterols on Angiotensin-Converting Enzyme and Nitric Oxide2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diet has for many years been known to play a key role in the development of chronic diseases. There are clear associations between consumption of vegetables, fruits and berries, and risk of cardiovascular diseases, the number one cause of death in the world. To maintain homeostasis of the vascular wall the balance between angiotensin II, nitric oxide and reactive oxygen species is of great importance in order to affect the development of cardiovascular diseases. Angiotensin II, a potent vasoconstrictor causing cell growth and nitric oxide, a signalling molecule influencing the vascular system as a vasodilatator, inhibiting cell proliferation and reactive oxygen species, are linked together in the renin-angiotensin aldosteron system. Angiotensin-converting enzyme will as a key enzyme in the reninangiotensin aldosteron system convert angiotensin I to form angiotensin II and nitric oxide is known to inhibit angiotensin-converting enzyme and act as a scavenger of reactive oxygen species. Plant-derived substances as flavonoids, tocopherols and carotenoids are shown to have beneficial effects on the cardiovascular system due to their antioxidative effects. The aims of this study were to investigate beverages, dietary products, herbal medicinal plants, α-tocopherol, β-carotene, sterols and lipidowering drugs on angiotensin-converting enzyme activity and nitric oxide concentrations. This was done to investigate if the sole mechanism of plant-derived substances is their antioxidative properties and to investigate if there is any connection between effect and biosynthesis/structure of plant substances. The tested infusions and extracts containing high amounts of flavonoids, the flavonoids and β-carotene significantly inhibited angiotensin-converting enzyme activity in vitro. The other substances tested did not affect, or in some cases significantly increased, angiotensin-converting enzyme activity. The infusions and extracts containing high amounts of flavonoids, the flavonoids andβ-carotene showed an increase on nitric oxide concentrations in vitro. Oral intake of a single dose of Rooibos tea significantly inhibited angiotensin-converting enzyme activity. A significant inhibition of angiotensin-converting enzyme activity was seen with the green tea for the angiotensin-converting enzyme genotypes II and ID. A significant inhibition of angiotensin-converting enzyme activity was also seen with the Rooibos tea for the angiotensin-converting enzyme genotype II.

    Conclusion; flavonoids and β-carotene interact with the cardiovascular system in severalways, by reducing reactive oxygen species (as shown in several studies), increasing nitricoxide concentrations (as shown here and by others) and also by inhibiting angiotensinconvertingenzyme activity (as shown here). Infusions and extracts as tea containing highamounts of flavonoids function as angiotensin-converting enzyme inhibitors. Angiotensinconvertingenzyme contains two zink-dependent catalytic domains and angiotensinconvertingenzyme inhibitors are designed to bind to the Zn2+ at the active site. If theinhibitory mechanism of flavonoids on angiotensin-converting enzyme activity is due to theirability to bind to Zn2+ ions then it would be possible for the flavonoids to also inhibit otherzinc metallopeptidases, i.e. endothelin-converting enzyme, matrix metallopeptidases, neutralendopeptidase and maybe insulin-degrading enzyme, thereby exerting several additionalpositive effects on the cardiovascular system.

    List of papers
    1. Tea flavanols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells
    Open this publication in new window or tab >>Tea flavanols inhibit angiotensin-converting enzyme activity and increase nitric oxide production in human endothelial cells
    2006 (English)In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 58, no 8, p. 1139-1144Article in journal (Refereed) Published
    Abstract [en]

    A diversity of pharmacological effects on the cardiovascular system have been reported for Camellia sinensis: antioxidative, antiproliferative and anti-angiogenic activity, and nitric oxide synthase activation. The purpose of this study was to investigate if the connection between tea and angiotensin-converting enzyme (ACE) and nitric oxide (NO) might be an explanation of the pharmacological effects of tea on the cardiovascular system. Cultured endothelial cells from human umbilical veins (HUVEC) were incubated with extracts of Japanese Sencha (green tea), Indian Assam Broken Orange Pekoe (black tea) and Rooibos tea, respectively. The main flavanols and purine alkaloids in green and black tea were examined for their effects on ACE and NO. After incubation with green tea, black tea and Rooibos tea for 10 min, a significant and dose-dependent inhibition of ACE activity in HUVEC was seen with the green tea and the black tea. No significant effect on ACE was seen with the Rooibos tea. After 10-min incubation with (-)-epicatechin, (-)- epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechingallate, a dose-dependent inhibition of ACE activity in HUVEC was seen for all four tea catechins. After 24-h incubation, a significantly increased dose-dependent effect on NO production in HUVEC was seen for the green tea, the black tea and the Rooibos tea. After 24-h incubation with (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechingallate and (-)-epigallocatechingallate, a dose-dependent increased NO production in HUVEC was seen. In conclusion, tea extracts from C. sinensis may have the potential to prevent and protect against cardiovascular disease. © 2006 The Authors.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-34910 (URN)10.1211/jpp.58.8.0016 (DOI)24032 (Local ID)24032 (Archive number)24032 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
    2. Effect of Panax ginseng extract (G115) on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) production
    Open this publication in new window or tab >>Effect of Panax ginseng extract (G115) on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) production
    2006 (English)In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 105, no 3, p. 321-325Article in journal (Refereed) Published
    Abstract [en]

    This study investigates the effects of the Panax ginseng (Araliaceae) extract G115 on angiotensin-converting enzyme (ACE) activity and nitric oxide (NO) in cultured human endothelial cells from umbilical veins (HUVEC) and bovine mesenteric arteries (BMA). In HUVEC, ACE activity was significantly reduced after 10 min incubation with aqueous extract of ginseng 5.0 and 10 mg/ml. This effect was additative with the inhibition of the traditional ACE inhibitor enalaprilat. No effect was seen on NO production from the cells. Angiotensin I-induced contraction of BMA was significantly attenuated by 0.1 and 0.5 mg/ml ginseng, while no endothelium-dependent or -independent relaxation was seen. In conclusion, extract of Panax ginseng (G115) inhibits ACE activity, but does not affect NO production in HUVEC and BMA. © 2005 Elsevier Ireland Ltd. All rights reserved.

    Keywords
    Panax ginseng; Angiotensin-converting enzyme; Nitric oxide; HUVEC
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-37111 (URN)10.1016/j.jep.2005.10.030 (DOI)33727 (Local ID)33727 (Archive number)33727 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2018-03-21Bibliographically approved
    3. Effects of Ginkgo biloba extract EGb 761 and its terpenelactones on angiotensin converting enzyme activity and nitric oxide production in human endothelial cells
    Open this publication in new window or tab >>Effects of Ginkgo biloba extract EGb 761 and its terpenelactones on angiotensin converting enzyme activity and nitric oxide production in human endothelial cells
    2008 (English)In: Journal of traditional medicines, ISSN 1880-1447, Vol. 3, no 2, p. 42-51Article in journal (Refereed) Published
    Abstract [en]

    The effects of Ginkga bi/aba (Ginkgoaceae), its terpene-Iactones (ginkgolide A, B, C and bilobalide), biflavonols (quercetin), biflavones (sciadopitysin) and proanthocyanidins (procyanidin) on angiotensin-converting enzyme (ACE) activity and nitric oxlde (NO) production in cultured human endothelial cells from umbilical veins (HUVEC) were investigated. A dose-dependent significant inhibition of the ACE activity was observed arter 10 min incubation with Ginkga bi/aba extract EGb  761 and quercetin. No significant effects due to terpene-Iactones or sciadopitysin were seen. Incubation with Ginkga bi/aba extract, quercetin, sciadopitysin and procyanidin for 24 hr significantly Increased NO production. No significant effects were seen with ginkgollde A, B and C, while bilobalide induced a dose-dependent decrease in NO production. In conclusion, this study shows that Ginkga bi/aba extract Inhibits ACE activlty and increases NO production from HUVEC. A flavonol (quercetin and/or homologs) is the main component responsible for the inhibitory effect ofACE activity. Quercetin and a proanthocyandin (procyanidin) are responsible for the increases seen in NO production. These results may explain the positive effects of Ginkga bi/aba on the cardiovascular system and on cognitive function.

    Keywords
    Angiotensin-converting enzyme; flavonoids; Ginkgo biloba; nitric oxide; terpene-lactones
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-44475 (URN)76784 (Local ID)76784 (Archive number)76784 (OAI)
    Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2011-01-11Bibliographically approved
    4. Effect of Vaccinium myrtillus and Its Polyphenols on Angiotensin-Converting Enzyme Activity in Human Endothelial Cells
    Open this publication in new window or tab >>Effect of Vaccinium myrtillus and Its Polyphenols on Angiotensin-Converting Enzyme Activity in Human Endothelial Cells
    2009 (English)In: Journal of Agricultural and Food Chemistry, ISSN 0021-8561, E-ISSN 1520-5118, Vol. 57, no 11, p. 4626-4629Article in journal (Refereed) Published
    Abstract [en]

    This study investigates if the connection between Vaccinium myrtillus and angiotensin-converting enzyme (ACE) might be an explanation of the pharmacological effects on circulation. Cultured endothelial cells from human umbilical veins were incubated with bilberry 25E extract. The main anthocyanidins combined in myrtillin chloride and separately in cyanidin, delphinidin, and malvidin, respectively, were examined concerning their effects on ACE. After 10 min of incubation with bilberry 25E, a significant, dose-dependent inhibition of ACE activity was seen, and after incubation with myrtillin chloride a significant inhibition was seen. No effect was seen with the anthocyanidins. The effect seems to be dependent on this specific mixture of anthocyanins in the bilberry. V. myrtillus may thus have the potential to prevent and protect against cardiovascular diseases.

    Keywords
    Angiotensin-converting enzyme; Vaccinium myrtillus; anthocyanidins
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-18654 (URN)10.1021/jf900128s (DOI)
    Note

    On the day of the defence date the status of this article was Submitted.

    Available from: 2009-06-03 Created: 2009-06-03 Last updated: 2018-03-27Bibliographically approved
    5. Effects of green tea, black tea and rooibos on angiotensin-converting enzyme activity in healthy volunteers
    Open this publication in new window or tab >>Effects of green tea, black tea and rooibos on angiotensin-converting enzyme activity in healthy volunteers
    2009 (English)In: in Planta Medica(ISSN 0032-0943), 2009, Vol. 75, no 9, p. 1030-1030Conference paper, Published paper (Refereed)
    Abstract [en]

    Tea has been reported to reduce cardiovascular mortality, but the mechanisms behind are largely unknown. The aim of this project was to investigate the effect of green tea (Japanese Sencha), black tea (Indian Assam B.O.P.) and Rooibos on angiotensin-converting enzyme and nitric oxide. Seventeen healthy volunteers received a single oral dose of either 400 ml green tea, black tea or Rooibos tea in a randomized three-phase cross over study. ACE activity and NO concentration were measured (at 0, 30, 60 and 180 minutes) in all phases. ACE activity was analysed with a commercial radioenzymatic assay. Nitrite was analysed as a marker of NO concentration. In addition ACE genotype was determined using a PCR method. Oral intake of a single dose of Rooibos significantly inhibited ACE activity, p<0.01 after 30 min and p<0.05 after 60 min. A significant inhibition of ACE activity was seen with green tea for the ACE genotype II (p<0.05), 30 minutes after intake of the tea and for the ACE genotype ID (p<0.05), 60 minutes after intake. A significant inhibition of ACE activity was also seen with Rooibos for the ACE genotype II (p<0.05), 60 minutes after intake. No significant effect on NO concentration was seen.

    Keywords
    Tea, angiotensin-converting enzyme, nitric oxide
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-20327 (URN)
    Note
    On the day of the defence date the status of this article was Submitted.Available from: 2009-09-04 Created: 2009-09-04 Last updated: 2011-03-31Bibliographically approved
  • 150.
    Persson, Ingrid
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Red wine, white wine, rosé wine, and grape juice inhibit angiotensin-converting enzyme in human endothelial cells2013In: International Journal of Nutrition, Pharmacology, Neurological Diseases, ISSN 2231-0738, Vol. 3, no 1, p. 17-23Article in journal (Refereed)
    Abstract [en]

    Background: Beneficial effects of wine on cardiovascular disease have been shown previously, but the mechanism is still unknown. The renin-angiotensin system is an important mechanism in the body concerning regulation of blood pressure, fluid, and electrolyte balance, and the angiotensin-converting enzyme (ACE) is a key enzyme in this system. Aims: The aim of this study was to investigate the effect of red wine, white wine, rosι wine, and alcohol-free grape juice on somatic ACE-1 activity. The effects of the stilbene resveratrol and its glycoside, resveratrol-3-glycoside were also tested on ACE activity and concentration of nitric oxide (NO). Materials and Methods: Cultured endothelial cells from human umbilical veins (HUVEC) were incubated with wine, grape juice, resveratrol, or resveratrol-3-glycoside. Ethanol was used as control in the corresponding concentration (13%). Results: After incubation, a significant inhibition of ACE activity was seen with all the wines tested and the red grape juice. This inhibition was of a similar magnitude except for a lesser inhibition with the rosι wine. No significant inhibition was seen with the white grape juice, resveratrol, resveratrol-3-glycoside, or ethanol alone, and neither did resveratrol nor resveratrol-3-glycoside affect the concentration of NO. Conclusions: The effect of wine and grape juice on ACE activity in HUVEC is dependent on the amount of flavonoids and not on the content of alcohol or resveratrol.

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