liu.seSearch for publications in DiVA
Change search
Refine search result
12 1 - 50 of 59
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1. Dare, E
    et al.
    Li, Wei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zhivotovsky, B
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Ceccatelli, S
    Methylmercury and H2O2 provoke lysosomal damage in human astrocytoma D384 cells followed by apoptosis2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 30, no 12, p. 1347-1356Article in journal (Refereed)
    Abstract [en]

    Methylmercury (MeHg) is a neurotoxic agent acting via diverse mechanisms, including oxidative stress. MeHg also induces astrocytic dysfunction, which can contribute to neuronal damage. The cellular effects of MeHg were investigated in human astrocytoma D384 cells, with special reference to the induction of oxidative-stress-related events. Lysosomal rupture was detected after short MeHg-exposure (1 ╡M, 1 h) in cells maintaining plasma membrane integrity. Disruption of lysosomes was also observed after hydrogen peroxide (H2O2) exposure (100 ╡M, 1 h), supporting the hypothesis that lysosomal membranes represent a possible target of agents causing oxidative stress. The lysosomal alterations induced by MeHg and H2O2 preceded a decrease of the mitochondrial potential. At later time points, both toxic agents caused the appearance of cells with apoptotic morphology, chromatin condensation, and regular DNA fragmentation. However, MeHg and H2O2 stimulated divergent pathways, with caspases being activated only by H2O2. The caspase inhibitor z-VAD-fmk did not prevent DNA fragmentation induced by H2O2, suggesting that the formation of high-molecular-weight DNA fragments was caspase independent with both MeHg and H2O2. The data point to the possibility that lysosomal hydrolytic enzymes act as executor factors in D384 cell death induced by oxidative stress. ⌐ 2001 Elsevier Science Inc.

  • 2.
    Daré, Elisabetta
    et al.
    The National Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Li, Wei
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Zhivotovsky, Boris
    The National Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Yuan, Ximing
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Ceccatelli, Sandra
    The National Institute of Environmental Medicine, Division of Toxicology and Neurotoxicology, Karolinska Institutet, Stockholm, Sweden.
    Methylmercury and H2O2 provoke lysosomal damage in human astrocytoma D384 cells followed by apoptosis2001In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 30, no 12, p. 1347-1356Article in journal (Refereed)
    Abstract [en]

    Methylmercury (MeHg) is a neurotoxic agent acting via diverse mechanisms, including oxidative stress. MeHg also induces astrocytic dysfunction, which can contribute to neuronal damage. The cellular effects of MeHg were investigated in human astrocytoma D384 cells, with special reference to the induction of oxidative-stress-related events. Lysosomal rupture was detected after short MeHg-exposure (1 μM, 1 h) in cells maintaining plasma membrane integrity. Disruption of lysosomes was also observed after hydrogen peroxide (H2O2) exposure (100 μM, 1 h), supporting the hypothesis that lysosomal membranes represent a possible target of agents causing oxidative stress. The lysosomal alterations induced by MeHg and H2O2 preceded a decrease of the mitochondrial potential. At later time points, both toxic agents caused the appearance of cells with apoptotic morphology, chromatin condensation, and regular DNA fragmentation. However, MeHg and H2O2 stimulated divergent pathways, with caspases being activated only by H2O2. The caspase inhibitor z-VAD-fmk did not prevent DNA fragmentation induced by H2O2, suggesting that the formation of high-molecular-weight DNA fragments was caspase independent with both MeHg and H2O2. The data point to the possibility that lysosomal hydrolytic enzymes act as executor factors in D384 cell death induced by oxidative stress.

  • 3.
    Eftekhari, S
    et al.
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Andersson, R
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    DYSFUNCTION AND APOPTOSIS OF ENDOTHELIAL CELLS VIA LYSOSOMAL DEATH PATHWAY in ATHEROSCLEROSIS SUPPLEMENTS, vol 10, issue 2, pp2009In: ATHEROSCLEROSIS SUPPLEMENTS, Elsevier Science B.V., Amsterdam. , 2009, Vol. 10, no 2Conference paper (Refereed)
    Abstract [en]

    n/a

  • 4.
    Garner, Brett
    et al.
    Department of Biomedical Science, University of Wollongong, Wollongong, NSW, Australia.
    Li, Wei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    On the cytoprotective role of ferritin in macrophages and its ability to enhance lysosomal stability1997In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 27, no 5, p. 487-500Article in journal (Refereed)
    Abstract [en]

    Macrophages have a great capacity to take up (eg. by endocytosis and phagocytosis) exogenous sources of iron which could potentially become cytotoxic, particularly following the intralysosomal formation of low-molecular weight, redox active iron, and under conditions of oxidative stress. Following autophago-cytosis of endogenous ferritin/apoferritin, these compounds may serve as chelators of such lysosomal iron and counteract the occurrence of iron-mediated intralysosomal oxidative reactions. Such redox-reactions have been shown to lead to destabilisation of lysosomal membranes and result in leakage of damaging lysosomal contents to the cytosol. In this study we have shown: (i) human monocyte-derived macrophages to accumulate ferritin in response to iron exposure; (ii) iron to destabilise macrophage secondary lysosomes when the cells are exposed to H2O2; and (iii) endocytosed apoferritin to act as a stabiliser of the acidic vacuolar compartment of iron-loaded macrophages. While the endogenous ferritin accumulation which was induced by iron exposure was not sufficient to protect cells from the damaging effects of H2O2, exogenously added apoferritin, as well as the potent iron chelator desferrioxamine, afforded significant protection. It is suggested that intralysosomal formation of haemosiderin, from partially degraded ferritin, is a protective strategy to suppress intralysosomal iron-catalysed redox reactions. However, under conditions of severe macrophage lysosomal iron-overload, induction of ferritin synthesis is not enough to completely prevent the enhanced cytotoxic effects of H2O2.

  • 5.
    Ghosh, Moumita
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Carlsson, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Laskar, Amit
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, XiMing
    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, Cardiology. Linköping University, Faculty of Health Sciences.
    Lysosomal membrane permeabilization causes oxidative stress and ferritin induction in macrophages2011In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 585, no 4, p. 623-9Article in journal (Refereed)
    Abstract [en]

    Moderate lysosomal membrane permeabilization (LMP) is an important inducer of apoptosis. Macrophages are professional scavengers and are rich in hydrolytic enzymes and iron. In the present study, we found that LMP by lysosomotropic detergent MSDH resulted in early up-regulation of lysosomal cathepsins, oxidative stress and ferritin up-regulation, and cell death. Lysosomotropic base NH(4)Cl reduced the ferritin induction and oxidative stress in apoptotic cells induced by MSDH. Cysteine cathepsin inhibitors significantly protected cell death and oxidative stress, but had less effect on ferritin induction. We conclude that oxidative stress induced by lysosomal rupture causes ferritin induction with concomitant mitochondrial damage, which are the potential target for prevention of cellular oxidative stress and cell death induced by typical lysosomotropic substances in different disorders.

  • 6.
    Johansson, Maria E.
    et al.
    Karolinska Institute, Sweden; University of Gothenburg, Sweden.
    Zhang, Xiao-Ying
    Karolinska Institute, Sweden; Peking University, Peoples R China.
    Edfeldt, Kristina
    Karolinska Institute, Sweden; Karolinska Institute, Sweden.
    Lundberg, Anna M.
    Karolinska Institute, Sweden.
    Levin, Malin C.
    University of Gothenburg, Sweden.
    Boren, Jan
    University of Gothenburg, Sweden.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Folkersen, Lasse
    Karolinska Institute, Sweden; Novo Nordisk, Denmark.
    Eriksson, Per
    Karolinska Institute, Sweden.
    Hedin, Ulf
    Karolinska Institute, Sweden.
    Low, Hann
    Baker IDI Heart and Diabet Institute, Australia.
    Sviridov, Dmitri
    Baker IDI Heart and Diabet Institute, Australia.
    Rios, Francisco J.
    Karolinska Institute, Sweden; University of Glasgow, Scotland.
    Hansson, Goran K.
    Karolinska Institute, Sweden.
    Yan, Zhong-Qun
    Karolinska Institute, Sweden.
    Innate immune receptor NOD2 promotes vascular inflammation and formation of lipid-rich necrotic cores in hypercholesterolemic mice2014In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 44, no 10, p. 3081-3092Article in journal (Refereed)
    Abstract [en]

    Atherosclerosis is an inflammatory disease associated with the activation of innate immune TLRs and nucleotide-binding oligomerization domain-containing protein (NOD)like receptor pathways. However, the function of most innate immune receptors in atherosclerosis remains unclear. Here, we show that NOD2 is a crucial innate immune receptor influencing vascular inflammation and atherosclerosis severity. 10-week stimulation with muramyl dipeptide (MDP), the NOD2 cognate ligand, aggravated atherosclerosis, as indicated by the augmented lesion burden, increased vascular inflammation and enlarged lipid-rich necrotic cores in Ldlr(-/-) mice. Myeloid-specific ablation of NOD2, but not its downstream kinase, receptor-interacting serine/threonine-protein kinase 2, restrained the expansion of the lipid-rich necrotic core in Ldlr(-/-) chimeric mice. In vitro stimulation of macrophages with MDP enhanced the uptake of oxidized low-density lipoprotein and impaired cholesterol efflux in concordance with upregulation of scavenger receptor A1/2 and downregulation of ATP-binding cassette transporter A1. Ex vivo stimulation of human carotid plaques with MDP led to increased activation of inflammatory signaling pathways p38 MAPK and NF-kappa B-mediated release of proinflammatory cytokines. Altogether, this study suggests that NOD2 contributes to the expansion of the lipid-rich necrotic core and promotes vascular inflammation in atherosclerosis.

  • 7. Jönsson, S
    et al.
    Bergström, I
    Li, Wei
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Nilsson,
    Jonasson, Lena
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Neutrophils- a potential source for increased serum MMP-9 in coronary artery disease.2009Conference paper (Refereed)
  • 8.
    Jönsson, Simon
    et al.
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Bergström, Ida
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Nilsson, L
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medicine and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    NEUTROPHILS - A POTENTIAL SOURCE FOR INCREASED SERUM MMP-9 IN CORONARY ARTERY DISEASE in ATHEROSCLEROSIS SUPPLEMENTS, vol 10, issue 2, pp2009In: ATHEROSCLEROSIS SUPPLEMENTS, Elsevier Science B.V., Amsterdam. , 2009, Vol. 10, no 2Conference paper (Refereed)
    Abstract [en]

    n/a

  • 9. Larsson, David A
    et al.
    Baird, Sarah
    Nyhalah, Jerome Diinga
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Li, Wei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Oxysterol mixtures, in atheroma-relevant proportions, display synergistic and proapoptotic effects2006In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 41, no 6, p. 902-910Article in journal (Refereed)
    Abstract [en]

    Apoptotic cells in atheroma lesions may contribute to plaque development and instability. Oxysterols constitute the major toxic component in oxLDL and are present in mixed forms in human atheroma lesions. However, the cellular effects of oxysterols have been mostly studied individually. In the present study, we investigated the cytotoxic effects of 7β-hydroxycholesterol (7βOH), 7-ketocholesterol (7keto), 25-hydroxycholesterol (25OH), and 27-hydroxycholesterol (27OH) on U937 monocytic cells, both individually and in atheroma-relevant mixtures mimicking the oxysterol composition reported in human atheroma lesions. Apoptosis and necrosis were studied by examining cell morphology, phosphatidylserine exposure, caspase activation, and the terminal dUTP nick end-labeling technique. Cellular reactive oxygen species and total amount of reduced thiols were measured by using fluorescence probes and 5,5′-dithiobis-(2-nitrobenzoic acid), respectively. We found that 7βOH and 7keto induced caspase activation, ROS production, cellular thiol depletion, permeabilization of lysosomal and mitochondrial membranes, and cell death. 25OH and 27OH did not cause any of the above alterations, whereas 7βOH and 7keto exerted synergistic toxic effects. Although single 25OH or 27OH exhibited quenching effects on both 7βOH- and 7keto-induced cell death, the combination of all four oxysterols in atheroma-relevant proportions was proapoptotic. Our findings indicate that the major oxysterols accumulated in human atheroma are proapoptotic and may contribute to atherosclerotic lesion development. © 2006 Elsevier Inc. All rights reserved.

  • 10.
    Laskar, Amit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf G G
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Fodipir (Dp-dp) and its dephosphorylated derivative PLED are involved in mangafodipir mediated cyto-protection against 7β-hydroxycholesterol induced cell death2013Manuscript (preprint) (Other academic)
    Abstract [en]

    Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolite of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent, dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7β-hydroxycholesterol (7βOH) induced cell death and identify the underlying mechanisms. U937 cells were pre-treated or not with mangafodipir substrate (Ms) (200 μm), MnPLED (100 μM) or Dp-dp (100 μM) for 8 hours and then exposed to 7βOH (28 μM) for 18 hours. Our results revealed that pre-treatment with MnPLED or Dp-dp protected against 7βOH induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dpdp in par with Ms, confer protection against 7βOH induced cytotoxicity by reducing  cellular ROS and stabilization of lysosomal membrane. These results suggest that, fodipir is the active part in mangafodipir, which shows the noted effects and its activity is conserved in MnPLED. These results further confirm the cyto-protective effect of mangafodipir and justify its potential use as a cyto-protective adjuvant.

  • 11.
    Laskar, Amit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Rolf
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Fodipir and Its Dephosphorylated Derivative Dipyridoxyl Ethyldiamine Are Involved in Mangafodipir-Mediated Cytoprotection against 7 beta-Hydroxycholesterol-Induced Cell Death2013In: Pharmacology, ISSN 0031-7012, E-ISSN 1423-0313, Vol. 92, no 3-4, p. 182-186Article in journal (Refereed)
    Abstract [en]

    Objective: Mangafodipir exerts pharmacological effects, including vascular relaxation and protection against oxidative stress and cell death induced by oxysterols. Additionally, mangafodipir has been proposed for cardiovascular imaging. The primary metabolites of mangafodipir, manganese dipyridoxyl ethyldiamine (MnPLED) and its constituent dipyridoxyl diphosphate (Dp-dp) also known as fodipir, are pharmacologically active. However, whether they affect oxysterol-induced cytotoxicity is currently unknown. In this study, we examine whether the mangafodipir metabolite affects 7 beta-hydroxycholesterol (7 beta-OH)-induced cell death and identify the underlying mechanisms. Methods: U937 cells were pretreated or not with mangafodipir substrate (Ms; 200 pm), MnPLED (100 mu mol/l) or Dp-dp (100 mu mol/l) for 8 h and then exposed to 7 beta-OH (28 mu mol/l) for 18 h. Results: Our results revealed that pretreatment with MnPLED or Dp-dp protected against 7 beta-OH-induced cellular reactive oxygen species (ROS) production, apoptosis, and lysosomal membrane permeabilization (LMP). MnPLED and Dp-dp, in par with Ms, confer protection against 7 beta-OH-induced cytotoxicity by reducing cellular ROS and stabilization of the lysosomal membrane. Conclusion: These results suggest that fodipir is the pharmacologically active part in the structure of mangafodipir, which prevents 7 beta-OH-induced cell death by attenuating cellular ROS and by preventing LMP. In addition, MnPLED, which is the dephosphorylated product of fodipir, exerts a similar protective effect against 7 beta-OH-induced cytotoxicity. This result indicates that dephosphorylation of fodipir does not affect its pharmacological actions. Altogether our result confirms the cytoprotective effect of mangafodipir and justifies its potential use as a cytoprotective adjuvant.

  • 12.
    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.

  • 13.
    Laskar, Amit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Ghosh, Moumita
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Iqbal Khattak, Sikander
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. 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.
    Degradation of superparamagnetic iron oxide nanoparticle-induced ferritin by lysosomal cathepsins and related immune response2012In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 7, no 5, p. 705-717Article in journal (Refereed)
    Abstract [en]

    Aim: To examine the physiological impact of superparamagnetic iron oxide nanoparticles (SPIONs) on cell function and its interaction with oxysterol laden cells. Materials andamp; methods: Intracellular iron was determined by Prussian blue staining. Cellular ferritin, cathepsin L and ferroportin were analyzed by flow cytometry and fluorescence microscopy. Cytokine secretion was determined by ELISA and immunoblotting. Results: In U937 and THP 1 cells, we did not detect any loss of cell viability on SPION loading. Desferrioxamine prevents induction of both ferritin and cathepsin L by SPIONs. Inhibition of lysosomal cathepsins upregulates both endogenous- and SPION-induced ferritin. SPION loading induces membranous ferroportin and incites secretion of ferritin, TNF-alpha and IL-10. 7 beta-hydroxycholesterol exposure reduces SPION uptake by cells. Conclusion: SPION loading results in upregulation of lysosomal cathepsin, membranous ferroportin and ferritin degradation, which is associated with secretion of both pro- and anti-inflammatory cytokines. A reduced SPION uptake by oxysterol-laden cells may lead to a compromised MRI with elevated cathepsins and ferritin.

  • 14.
    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.

  • 15.
    Laskar, Amit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, XiMing
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Dimethyl Sulfoxide Prevents 7 beta-Hydroxycholesterol-Induced Apoptosis by Preserving Lysosomes and Mitochondria2010In: JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, ISSN 0160-2446, Vol. 56, no 3, p. 263-267Article in journal (Refereed)
    Abstract [en]

    Dimethyl sulfoxide (DMSO) is a widely used vehicle for water-insoluble substances and exerts a wide range of pharmacologic effects including anti-inflammatory and free radical scavenging properties. Additionally, in an animal model, DMSO inhibited cholesterol- induced atherosclerosis. Despite such profound pharmacologic effects, mechanisms at the cellular level are not well understood. Atherogenic oxysterols, especially 7-oxysterols, are potent inducers of oxidative stress, cell apoptosis, and are elevated in human atherosclerotic lesions. In this study, we first investigated the effect of DMSO on 7 beta-hydroxycholesterol-induced apoptosis of U937 cells and then focused on its influences on production of reactive oxygen species, lysosomal, and mitochondrial membrane permeability. Our results revealed that DMSO protected U937 cells against 7 beta-hydroxycholesterol- induced cell death by preventing lysosomal and mitochondrial membrane permeabilization and reactive oxygen species production. Our results also emphasize the necessity for appropriate solvent control groups in experimental models in which DMSO has been used to examine drug effect or identify pathways.

  • 16.
    Li, Wei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Oxidative stress, macrophages, iron, and atherosclerosis1997Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Macrophages have a great capacity to take up exogenous material, such as oxidatively modified low density lipoproteins (oxLDL) and different sources of iron containing structures. OxLDL is taken up into macrophage lysosomes by receptor-mediated endocytosis, but poorly degraded, resulting in foam-cell formation. The foam cell formation and the cytotoxicity of oxLDL to several arterial wall cells might contribute to atherogenesis. The iron sequestrated by macrophages could potentially become cytotoxic, particularly following intralysosomal accumulation of low-molecular weight iron in a redox-active form, and under conditions of oxidative stress. Following autophagocytosis, endogenous ferritin/apoferritin may serve as chelators of such lysosomal iron and counteract the occurrence of iron-mediated intra-lysosomal oxidative reactions.

    In the present study, we estimated the influence of oxLDL on lysosomal enzyme activity, lysosomal membrane stability, and the modulation of these cellular characteristics by high density lipoprotein (HDL) and vitamin E (vit-E). We also examined iron-stimulated ferritin synthesis, and the effects of exogenously added apoferritin on cells and lysosomal membrane stability following oxidative stress. Human monocyte-derived macrophages and J-774 cells were used in the study. The activities of the lysosomal enzymes, cathepsin-L and N-acetyl-ß-glucosarninidase (NAßGase), were biochemically assayed on cellular fractions. The lysosomal integrity was estimated by an acridine orange (AO) vital staining test as well as by immunocytochemical cathepsin-D demonstration. Cellular ferritin was assayed by ELISA, and lysosomal iron was demonstrated by autometallography and transmission electron microscopy.

    We found that the total activities of NAßGase and cathepsin-L were significantly decreased, whereas their relative cytosolic activities were enhanced after oxLDL-exposure. Labilization of the lysosomal membranes was further proven by a decreased lysosomal AO-uptake and a relocation to the cytosol of cathepsin-D. as estimated by light- and electron microscopic immunocytochemistry. HDL and vit-E diminished the cytotoxicity of oxLDL by decreasing the lysosomal damage. The synthesis and accumulation of ferritin in HMDM are responses to the iron-exposure, but ferritin is not efficient enough to protect the lysosomes from oxidative stress. Endocytosed apoferritin acts as a stabilizer of the acidic vacuolar compartment of iron-loaded macrophages.

  • 17.
    Li, Wei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Oxidized Lipids and Lysosomal Pathology in Atherogenesis2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Macrophages take up large amount of exogenous materials such as oxidatively modified low-density lipoproteins (oxLDL) and lysosomotropic agents. OxLDL is taken up into macrophage lysosomes through receptor-mediated endocytosis, but poorly degraded, resulting in foam cell formation. Cholesterol oxidation products, major toxic components of oxLDL, are involved in foam cell formation and the initiation of atherosclerosis. The production of ROS/RNS, cytokines, and matrix proteases by macrophages and the apoptosis of arterial cells may contribute to atherosclerotic plaque development and destabilization.

    We had four objectives in this study, first we study the influence of oxLDL on lysosomal membrane stability, location and activity of lysosomal enzymes, macrophage cell death, and the modulation of these cellular characteristics by high-density lipoprotein (HDL), vitantin E (vit E), and the iron chelator desferrioximine (DFO) or iron complex. Second, we examined the role of lysosomal enzymes in macrophage apoptosis induced by oxysterols, the major cytotoxic components of oxLDL. Third, we analyzed the expression of cysteine protease cathepsins B and L and studied their relationship to macrophage apoptosis in human atherosclerotic lesions. And fourth, we investigated whether lysosomal rupture and release of lysosomal enzymes could initiate apoptosis using the lysosomotropic detergent MSDH.

    The results suggest that oxLDL causes lysosomal destabilization and relocation of lysos'omal enzymes as indicated by increased cytosolic NABGase, cathepsin-L, and cathepsin D, and decreased lysosomal acridine orange (AO)-induced red fluorescence. AcLDL had no cytotoxic effects on the cells and their lysosomes. HDL, vit E, and the iron chelator DFO diminished the cytotoxicity of oxLDL by decreasing lysosomal damage, while the iron complex enhanced oxLDL cytotoxicity. Macrophage apoptosis induced by ChOx and 7-oxysterols (7B-OH and 7- keto) is associated with lysosomal rupture and release of lysosomal enzymes to the cytosol. The lysosomal punctuated immune-granularity of cathepsins B and L was decreased in 7 -oxysteroltreated cells compared to control cells. Moreover, there is enhancement and dispersion of cathepsins B and L immunoreactivity throughout 7-oxysterols-treated cells and an extensive immunoreaction in the nuclei and around nuclear areas of apoptotic cells. Using MSDH, a lysosomotropic detergent, we further demonstrated that lysosomal rupture and release of lytic enzymes indeed play an initial role in macrophage apoptosis.

    There is a lesion dependent eo-expression of cathepsins B and Land caspase-3 in early and advanced human atherosclerotic lesions, which is associated with macrophage apoptosis.

    We conclude that macrophage cell death including apoptosis induced by oxLDL and oxysterols is associated with lysosomal rupture and relocation of lysosomal hydrolytic enzymes to the cytosol. The released enzymes may initiate ceU death by activating the caspase cascade, attacking mitochondria, or directly attacking the nuclear of the cells. The high eo-expression of cathepsins B and L with caspase-3 in apoptotic macrophages in human atheroma lesions suggests that macrophage apoptosis and related hydrolytic enzymes may play an important role in lesion development and plaque instability.

    List of papers
    1. Uptake of Oxidized LDL by Macrophages Results in Partial Lysosomal Enzyme Inactivation and Relocation
    Open this publication in new window or tab >>Uptake of Oxidized LDL by Macrophages Results in Partial Lysosomal Enzyme Inactivation and Relocation
    1998 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 18, no 2, p. 177-84Article in journal (Refereed) Published
    Abstract [en]

    The cytotoxicity of oxidized LDL (oxLDL) to several types of artery wall cells might contribute to atherosclerosis by causing cell death, presumably by both apoptosis and necrosis. After its uptake into macrophage lysosomes by receptor-mediated endocytosis, oxLDL is poorly degraded, resulting in ceroid-containing foam cells. We studied the influence of oxLDL on lysosomal enzyme activity and, in particular, on lysosomal membrane stability and the modulation of these cellular characteristics by HDL and vitamin E (vit-E). Unexposed cells and cells exposed to acetylated LDL (AcLDL) were used as controls. The lysosomal marker enzymes cathepsin L and N-acetyl-β-glucosaminidase (NAβGase) were biochemically assayed in J-774 cells after fractionation. Lysosomal integrity in living cells was assayed by the acridine orange (AO) relocation test. Cathepsin D was immunocytochemically demonstrated in J-774 cells and human monocyte-derived macrophages. We found that the total activities of NAβGase and cathepsin L were significantly decreased, whereas their relative cytosolic activities were enhanced, after oxLDL exposure. Labilization of the lysosomal membranes was further proven by decreased lysosomal AO uptake and relocation to the cytosol of cathepsin D, as estimated by light and electron microscopic immunocytochemistry. HDL and vit-E diminished the cytotoxicity of oxLDL by decreasing the lysosomal damage. The results indicate that endocytosed oxLDL not only partially inactivates lysosomal enzymes but also destabilizes the acidic vacuolar compartment, causing relocation of lysosomal enzymes to the cytosol. Exposure to AcLDL resulted in its uptake with enlargement of the lysosomal apparatus, but the stability of the lysosomal membranes was not changed.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-65822 (URN)10.1161/​01.ATV.18.2.177 (DOI)9484981 (PubMedID)
    Available from: 2011-02-21 Created: 2011-02-21 Last updated: 2017-12-11Bibliographically approved
    2. OxLDL-induced macrophage cytotoxicity is mediated by lysosomal rupture and modified by intralysosomal redox-active iron
    Open this publication in new window or tab >>OxLDL-induced macrophage cytotoxicity is mediated by lysosomal rupture and modified by intralysosomal redox-active iron
    1998 (English)In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 29, no 5, p. 389-98Article in journal (Refereed) Published
    Abstract [en]

    Oxidized low density lipoprotein (oxLDL) is believed to play a central role in atherogenesis. LDL is oxidized in the arterial intima by mechanisms that are still only partially understood. OxLDL is then taken up by macrophages through scavenger receptor-mediated endocytosis, which then leads to cellular damage, including apoptosis. The complex mechanisms by which oxLDL induces cell injury are mostly unknown. This study has demonstrated that oxLDL-induced damage of macrophages is associated with iron-mediated intralysosomal oxidative reactions, which cause partial lysosomal rupture and ensuing apoptosis. This series of events can be prevented by pre-exposing cells to the iron-chelator, desferrioxamine (DFO), whereas it is augmented by pretreating the cells with a low molecular weight iron complex. Since both DFO and the iron complex would be taken up by endocytosis, and thus directed to the lysosomal compartment, the results suggest that the normal contents of lysosomal low molecular weight iron may play an important role in oxLDL-induced cell damage, presumably by catalyzing intralysosomal fragmentation of lipid peroxides and the formation of toxic aldehydes and oxygen-centered radicals.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-65821 (URN)10.1080/10715769800300431 (DOI)9925031 (PubMedID)
    Available from: 2011-02-21 Created: 2011-02-21 Last updated: 2017-12-11Bibliographically approved
    3. Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products
    Open this publication in new window or tab >>Lysosomal destabilization during macrophage damage induced by cholesterol oxidation products
    Show others...
    2000 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 28, no 2, p. 208-218Article in journal (Refereed) Published
    Abstract [en]

    We have previously shown that oxidized low-density lipoprotein (LDL) induces damage to the macrophage lysosomal membranes, with ensuing leakage of lysosomal contents and macrophage cell death. Cholesterol oxidation products (ChOx) have been reported to be the major cytotoxic components of oxidized LDL/LDL and also to stimulate cholesterol accumulation in vascular cells. In the present study, we characterized the initial events during macrophage damage induced by cholesterol oxidation products (ChOx). Within 24 h of exposure, ChOx caused lysosomal destabilization, release to the cytosol of the lysosomal marker-enzyme cathepsin D, apoptosis, and postapoptotic necrosis. Enhanced autophagocytosis and chromatin margination was found 12 h after the exposure to ChOx, whereas apoptosis and postapoptotic necrosis was pronounced 24 and 48 h after the exposure. Some lysosomal vacuoles were then filled with degraded cellular organelles, indicating phagocytosis of apoptotic bodies by surviving cells. Because caspase-3 activation was detected in the ChOx-exposed cells, lysosomal destabilization may associate with the leakage of lysosomal enzymes, and activation of the caspase cascade. MnSOD mRNA levels were markedly increased after 24 h of exposure to ChOx, suggesting associated induction of mitochondrial protection repair or turnover. We conclude that ChOx-induced damage to lysosomes and mitochondria are sequelae to the cascade of oxysterol cytotoxic events. The early disruption of lysosomes induced by ChOx, with resultant autophagocytosis may be a critical event in apoptosis and/or necrosis of macrophages/foam cells during the development of atherosclerotic lesions.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-27688 (URN)10.1016/S0891-5849(99)00220-8 (DOI)12426 (Local ID)12426 (Archive number)12426 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    4. Apoptotic Death of Inflammatory Cells in Human Atheroma
    Open this publication in new window or tab >>Apoptotic Death of Inflammatory Cells in Human Atheroma
    2001 (English)In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 21, no 7, p. 1124-1130Article in journal (Refereed) Published
    Abstract [en]

    Although the accumulation of cholesterol and other lipidic material is unquestionably important in atherogenesis, the reasons why this material progressively accumulates, rather than being effectively cleared by phagocytic cells such as macrophages, are not completely understood. We hypothesize that atheromatous lesions may represent "death zones" that contain toxic materials such as oxysterols and in which monocytes/macrophages become dysfunctional and apoptotic. Indeed, cathepsins B and L, normally confined to the lysosomal compartment, are present in the cytoplasm and nuclei of apoptotic (caspase-3-positive) macrophages within human atheroma. The possible involvement of oxysterols is suggested by experiments in which cultured U937 and THP-1 cells exposed to 7-oxysterols similarly undergo marked lysosomal destabilization, caspase-3 activation, and apoptosis. Like macrophages within atheroma, intralysosomal cathepsins B and L are normally present in the cytoplasm and nuclei of these oxysterol-exposed cells. Lysosomal destabilization, cathepsin release, and apoptosis may be causally related, because inhibitors of cathepsins B and L suppress oxysterol-induced apoptosis. Thus, toxic materials such as 7-oxysterols in atheroma may impair the clearance of cholesterol and other lipidic material by fostering the apoptotic death of phagocytic cells, thereby contributing to further development of atherosclerotic lesions.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-27724 (URN)10.1161/​hq0701.092145 (DOI)12463 (Local ID)12463 (Archive number)12463 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    5. Induction of cell death by the lysosomotropic detergent MSDH
    Open this publication in new window or tab >>Induction of cell death by the lysosomotropic detergent MSDH
    Show others...
    2000 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 470, no 1, p. 35-39Article in journal (Refereed) Published
    Abstract [en]

    Controlled lysosomal rupture was initiated in lysosome-rich, macrophage-like cells by the synthetic lysosomotropic detergent, O-methyl-serine dodecylamide hydrochloride (MSDH). When MSDH was applied at low concentrations, resulting in partial lysosomal rupture, activation of pro-caspase-3-like proteases and apoptosis followed after some hours. Early during apoptosis, but clearly secondary to lysosomal destabilization, the mitochondrial transmembrane potential declined. At high concentrations, MSDH caused extensive lysosomal rupture and necrosis. It is suggested that lysosomal proteases, if released to the cytosol, may cause apoptosis directly by pro-caspase activation and/or indirectly by mitochondrial attack with ensuing discharge of pro-apoptotic factors.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-27689 (URN)10.1016/S0014-5793(00)01286-2 (DOI)12427 (Local ID)12427 (Archive number)12427 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 18.
    Li, Wei
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    THE 7B-HYDROXYCHOLESTEROL INDUCES HUMAN NATURAL KILLER CELL DEATH VIA OXIDATIVE STRESS RELATED LYSOSOMAL DESTABILIZATION in ATHEROSCLEROSIS SUPPLEMENTS, vol 10, issue 2, pp2009In: ATHEROSCLEROSIS SUPPLEMENTS, Elsevier Science B.V., Amsterdam. , 2009, Vol. 10, no 2Conference paper (Refereed)
    Abstract [en]

    n/a

  • 19.
    Li, Wei
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Dalen, Helge
    Department of Pathology, Gade Institute, University of Bergen, Bergen, Norway.
    Eaton, John Wallace
    The James Graham Brown Cancer Center, University of Louisville, Louisville, Ky.
    Yuan, Xi Ming
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Apoptotic Death of Inflammatory Cells in Human Atheroma2001In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 21, no 7, p. 1124-1130Article in journal (Refereed)
    Abstract [en]

    Although the accumulation of cholesterol and other lipidic material is unquestionably important in atherogenesis, the reasons why this material progressively accumulates, rather than being effectively cleared by phagocytic cells such as macrophages, are not completely understood. We hypothesize that atheromatous lesions may represent "death zones" that contain toxic materials such as oxysterols and in which monocytes/macrophages become dysfunctional and apoptotic. Indeed, cathepsins B and L, normally confined to the lysosomal compartment, are present in the cytoplasm and nuclei of apoptotic (caspase-3-positive) macrophages within human atheroma. The possible involvement of oxysterols is suggested by experiments in which cultured U937 and THP-1 cells exposed to 7-oxysterols similarly undergo marked lysosomal destabilization, caspase-3 activation, and apoptosis. Like macrophages within atheroma, intralysosomal cathepsins B and L are normally present in the cytoplasm and nuclei of these oxysterol-exposed cells. Lysosomal destabilization, cathepsin release, and apoptosis may be causally related, because inhibitors of cathepsins B and L suppress oxysterol-induced apoptosis. Thus, toxic materials such as 7-oxysterols in atheroma may impair the clearance of cholesterol and other lipidic material by fostering the apoptotic death of phagocytic cells, thereby contributing to further development of atherosclerotic lesions.

  • 20.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Hellsten, Anna
    Linköping University, Department of Biomedicine and Surgery.
    Jacobsson, Leif
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Blomqvist, Henrik
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine.
    Olsson, Anders
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Internal Medicine. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Alpha-tocopherol and astaxanthin decrease macrophage infiltration, apoptosis and vulnerability in atheroma of hyperlipidaemic rabbits2004In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 37, no 5, p. 969-978Article in journal (Refereed)
    Abstract [en]

    The composition of atherosclerotic plaques, not just macroscopical lesion size, has been implicated in their susceptibility to rupture and the risk of thrombus formation. By focusing on the quality of lipids, macrophages, apoptosis, collagen, metalloproteinase expression and plaque integrity, we evaluated the possible anti-atherosclerotic effect of the antioxidants α-tocopherol and astaxanthin in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one WHHL rabbits were divided into three groups and were fed a standard diet, as controls (N =10), or a standard diet with the addition of 500 mg α-tocopherol per kg feed (N =11) or 100 mg astaxanthin per kg feed (N =10) for 24 weeks. We found that both antioxidants, particularly astaxanthin, significantly decreased macrophage infiltration in the plaques although they did not affect lipid accumulation. All lesions in the astaxanthin-treated rabbits were classified as early plaques according to the distribution of collagen and smooth muscle cells. Both antioxidants also improved plaque stability and significantly diminished apoptosis, which mainly occurred in macrophages, matrix metalloproteinase three expressions and plaque ruptures. Although neither antioxidant altered the positive correlations between the lesion size and lipid accumulation, the lesion size and apoptosis were only positively correlated in the control group. Astaxanthin and α-tocopherol may improve plaque stability by decreasing macrophage infiltration and apoptosis in this atherosclerotic setting. Apoptosis reduction by α-tocopherol and astaxanthin may be a new anti-atherogenic property of these antioxidants. © 2004 Elsevier Ltd. All rights reserved.

  • 21.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Hellsten, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery.
    Nyhalah, JD
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Enhanced expression of natural resistance-associated macrophage protein 1 in atherosclerotic lesions may be associated with oxidized lipid-induced apoptosis2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 202-207Article in journal (Refereed)
    Abstract [en]

    The natural resistance-associated macrophage proteins (Nramps) can modulate inflammatory reactions. Nramps are not only responsible for intracellular divalent metal transport but also determine the macrophage functions in inflammatory processes. In the present study we tested whether Nramp1 is involved in macrophage apoptosis induced by oxidized lipids in atherogenesis. Arterial segments of Watanabe heritable hyperlipidemic rabbits were used for an examination of Nramp1 mRNA by in situ RT-PCR and macrophage immunohistochemistry. Annexin V/PI staining and terminal dUTP nick-end labeling (TUNEL) techniques were used for apoptosis detection. We found that, in macrophage-rich areas (positive to RMA-11) of the rabbit atherosclerotic aorta, there were lesion-dependent increases in Nramp1 mRNA, which are mainly apoptotic foamy macrophages that are positive to TUNEL staining. U937 cells were treated with 7 beta-hydroxycholesterol (7 beta-OH) in the presence or absence of the redox-active iron chelator desferrioxamine (DFO) or 1,10-phenanthroline. The cellular iron chelators considerably reduced, whereas iron compounds enhanced, 7 beta-OH-induced apoptosis and necrosis. DFO also decreased mRNA levels of Nramp1, whereas both iron compounds and 7 beta-OH dramatically enhanced the expression of Nramp1 mRNA, particularly among 7 beta-OH-induced apoptotic cells. We conclude that the enhanced expression of Nramp1 in macrophage regions of atherosclerotic lesions may be associated with ferrous iron-enhanced, oxidized lipid-induced apoptosis. This finding reveals a novel function of Nramp1 in atherogenesis.

  • 22.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Hellsten, Anna
    Linköping University, Department of Neuroscience and Locomotion. Linköping University, Faculty of Health Sciences.
    Xu, Lihua
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Zhuang, D-M
    Jansson, Katarina
    Brunk, Ulf
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Foam cell death induced by 7β-hydroxycholesterol is mediated by labile iron-driven oxidative injury: Mechanisms underlying induction of ferritin in human atheroma2005In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 39, no 7, p. 864-875Article in journal (Refereed)
    Abstract [en]

    Human atherosclerotic lesions typically contain large amounts of ferritin associated with apoptotic macrophages and foam cells, although the reasons are unknown. In the present investigation, we studied the relationship between ferritin induction and occurrence of apoptosis in 7β-hydroxycholesterol (7β-OH)-treated monocytic cells and macrophages. We found that 7β-OH enlarges the intracellular labile iron pool, increases formation of reactive oxygen species (ROS), and induces ferritin and cytosolic accumulation of lipid droplets, lysosomal destabilization, and apoptototic macrophage death. Since ferritin is a phase II-type protective protein, our findings suggest that ferritin upregulation here worked as an inefficient defense mechanism. Addition to the culture medium of both a membrane-permeable iron chelator 10-phenanthroline and the non-membrane-permeable iron chelators apoferritin and desferrioxamine afforded significant protection against the 7β-OH-induced effects. Consequently, endocytosed iron compounds dramatically augmented 7β-OH-induced cytotoxicity. We conclude that oxidized lipid 7β-OH causes not only foam cell formation but also oxidative damage with abnormal metabolism of cellular iron. The findings suggest that modulation of iron metabolism in human atheroma may be a potential therapeutic strategy against atherosclerosis. © 2005 Elsevier Inc. All rights reserved.

  • 23.
    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.

  • 24.
    Li, Wei
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical 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, Ximing
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    7-beta-hydroxycholesterol induces natural killer cell death via oxidative lysosomal destalization.2009Conference paper (Refereed)
  • 25.
    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.

  • 26.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kornmark, Louise
    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, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Forssell, Claes
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Cathepsin L is significantly associated with apoptosis and plaque destabilization in human atherosclerosis2009In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 202, no 1, p. 92-102Article in journal (Refereed)
    Abstract [en]

    Objective: Human atherosclerotic lesions overexpress elastolytic and collagenolytic cathepsins with unclear pathological implications. The aim of this study was to investigate the relationship among expression of cathepsin L. macrophage apoptosis in coronary artery disease (CAD) patients, clinical symptoms and plaque severity Of human carotid atheroma.

    Methods and results: Quantitative immunohistochemical analysis of human carotid atherosclerotic lesions (n = 49) showed that expression of lysosomal cathepsin L was significantly increased in atherosclerotic plaques with formation of the necrotic core and rupture of the cap. In those Plaques, cathepsin L was associated mainly with CD68-positive macrophages, whereas significant lower levels of smooth muscle cell actin were detected. The expression of cathepsin L in these plaques was also correlated with apoptosis and the stress protein ferritin. Plaques from symptomatic patients showed greater increased levels of cathepsin L than those front asymptomatic patients. Human monocyte-derived macrophages from CAD patients (n = 7) showed significantly higher levels of cathepsin L, cellular lipids and apoptosis versus cells from matched healthy donors (n = 7). 7Beta-hydroxycholesterol significantly enhanced cathepsin L in cells from healthy donors but not in Cells from CAD patients. Moreover. macrophage apoptosis was significantly correlated with expression of cathepsin L in cell nuclei and membranes.

    Conclusion: The results Suggest that cathepsin L is involved in death of macrophages necrotic Core formation and development of atherosclerotic plaque instability. Macrophage lysosomal cathepsin L and related apoptosis may be potential targets for modulation or imaging of vulnerable plaques in human atherosclerosis.

  • 27.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Laskar, Amit
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Sultana, Nargis
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Osman, Ehab
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Ghosh, Moumita
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Li, Qianqian
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    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.
    Cell death induced by 7-oxysterols via lysosomal and mitochondrial pathways is p53-dependent2012In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 53, no 11, p. 2054-2061Article in journal (Refereed)
    Abstract [en]

    Oxysterol accumulation and p53 expression mainly in macrophages have been associated with cell death and necrotic core formation in human atheroma progression. Oxidative stress and lysosomal membrane permeabilization (LMP) in macrophages are important causes of macrophage apoptosis. However, it is not understood how p53 and oxysterols interact in the process. We show here that 7-oxysterols induce endogenous full-length p53 and phospho-p53 (p53-Ser15) in both nucleus and cytoplasm of THP1 and J774 cells, which is followed by cellular oxidative stress and apoptotic cell death. The role of p53 in 7-oxysterol-mediated cell death is further investigated in temperature sensitive p53-transfected (M1-t-p53) and in p53-deficient (M1) cells. These results reveal that 7-oxysterols induce induction and nuclear translocation of p53 in M1-t-p53 cells, which in turn enhances LMP, mitochondrial translocation of Bax, mitochondrial membrane permeabilization, cytosolic release of cytochrome c, and cell death. Most importantly, the above effects of 7-oxysterols were not observed in p53-deficient M1 cells. The findings reveal that 7-oxysterol-induced cell death occurs via p53-dependent pathways. Subsequent p53 nuclear translocation and induction of wild-type and phosphorylated p53 are early steps in oxysterol-induced lysosomal-mitochondrial pathways involved in cell death.

  • 28.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lidebjer, Caroline
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Szymanowski, Aleksander
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Backteman, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Immunology and Transfusion Medicine.
    Leanderson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine Centre.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology.
    Swahn, Eva
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Jonasson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    NK cell apoptosis in coronary artery disease. Relation to oxidative stress2008In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 199, no 1, p. 65-72Article in journal (Refereed)
    Abstract [en]

    Objective: Natural killer (NK) cells, key elements in initiation and modulation of immune responses, were recently found to be reduced in coronary artery disease (CAD). To clarify mechanisms behind this reduction, we here investigated NK cell apoptosis in CAD patients. Since oxidative stress has been linked to NK cell apoptosis, we related the findings to oxidative stress in vivo and evaluated the ex vivo susceptibility of NK cells to oxidized lipids. Methods and results: The number of apoptotic NK cells in peripheral blood was significantly increased in CAD patients compared to controls. Purified NK cells from CAD patients also showed a higher rate of spontaneous apoptosis ex vivo. Dose- and time-dependent effects of oxidized LDL and 7β-hydroxycholesterol (7βOH) on apoptosis and ROS production were determined in NK cells from blood donors. Thereafter, purified NK cells from CAD patients and healthy controls were exposed to the oxidized lipids in a paired design. NK cells from patients were more susceptible to apoptosis induced by oxidized LDL, in particular 7βOH, compared to cells from controls. Plasma measurements of LDL protein oxidation and lipid peroxidation did not show any differences between patients and controls. On the other hand, plasma carotenoids were significantly decreased in patients and inversely correlated to NK cell apoptosis rate. Conclusion: The rate of spontaneous NK cell apoptosis was increased in CAD patients. Although NK cells in CAD patients were more sensitive to oxidized lipids ex vivo, indicating a mechanism contributing to the reduced NK cell activity in CAD, the data could not verify an obvious link between NK cell apoptosis and increased oxidative stress in vivo. © 2007 Elsevier Ireland Ltd. All rights reserved.

  • 29.
    Li, Wei
    et al.
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Miah, S
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Jönsson, Simon
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Andersson, R
    Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    APOPTOSIS INDUCED BY 7B-HYDROXYCHOLESTEROL IS ASSOCIATED WITH REGULATION OF P53, B-CATENIN, AND EGR-1 in ATHEROSCLEROSIS SUPPLEMENTS, vol 10, issue 2, pp2009In: ATHEROSCLEROSIS SUPPLEMENTS, Elsevier Science B.V., Amsterdam. , 2009, Vol. 10, no 2Conference paper (Refereed)
    Abstract [en]

    n/a

  • 30.
    Li, Wei
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Osman, Ehab
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Forssell, C
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    THROMBIN RECEPTOR (PAR1), TISSUE FACTOR AND IRON BINDING PROTEINS IN HUMAN CAROTID ATHEROSCLEROSIS2009In: ATHEROSCLEROSIS SUPPLEMENTS, Elsevier, 2009, Vol. 10, no 2, p. e595-e595Conference paper (Other academic)
  • 31.
    Li, Wei
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Xu, Lihua
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology.
    Forssell, C.
    Sullivan, J.L.
    Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32816.
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Overexpression of transferrin receptor and ferritin related to clinical symptoms and destabilization of human carotid plaques2008In: Experimental biology and medicine (Maywood, N.J.: Print), ISSN 1535-3702, E-ISSN 1535-3699, Vol. 233, no 7, p. 818-826Article in journal (Refereed)
    Abstract [en]

    Accumulation of tissue iron has been implicated in development of atherosclerotic lesions mainly because of increased iron-catalyzed oxidative injury. However, it remains unknown whether cellular iron import and storage in human atheroma are related to human atheroma development. We found that transferrin receptor 1 (TfR1), a major iron importer, is highly expressed in foamy macrophages and some smooth muscle cells in intimal lesions of human carotid atheroma, mainly in cytoplasmic accumulation patterns. In 52 human carotid atherosclerotic lesions, TfR1 expression was positively correlated with macrophage infiltration, ectopic lysosomal cathepsin L, and ferritin expression. Highly expressed TfR1 and ferritin in CD68-positive macrophages were significantly associated with development and severity of human carotid plaques, smoking, and patient's symptoms. The findings suggest that pathologic macrophage iron metabolism may contribute to vulnerability of human atheroma, established risk factors, and their clinical symptoms. The cytoplasmic overexpression of TfR1 may be the result of lysosomal dysfunction and ectopic accumulation of lysosomal cathepsin I caused by atheroma-relevant lipids in atherogenesis. Copyright © 2008 by the Society for Experimental Biology and Medicine.

  • 32.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences.
    Xu, Lihua
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology .
    Yuan, Ximing
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Macrophage hemoglobin scavenger receptor and ferritin accumulation in human atherosclerotic lesions2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 196-201Article in journal (Refereed)
    Abstract [en]

    We previously proposed that erythrophagocytosis and iron metabolism by macrophages may contribute to iron-driven oxidative stress in atherogenesis. Recent studies have indicated that the macrophage hemoglobin scavenger receptor (HbSR/CD 163) is a key molecule in the process of removing hemoglobin released from senescent erythrocytes. In this study we investigated crythrophagocytosis and its relation to ferritin accumulation and the involvement of CD163 in ferritin induction in human atheroma lesions. Normal and atherosclerotic human arterial segments obtained at autopsy and surgery were collected for iron histochemistry, hemoglobin and ferritin immunohistochemistry, and computerized image analysis. The lesion-dependent accumulation of ferritin and hemoglobin was seen in atherosclerotic carotid and coronary arteries. The immunoreactivity of hemoglobin was significantly correlated to the same regions of ferritin immunoreactivity on serial sections. The staining intensity of hemoglobin and ferritin was also significantly correlated. Hemoglobin deposition is often associated with microvessels adjacent to the lipid core areas in advanced lesions, where most CD68-positive macrophages were. CD163 expression appeared in both early and advanced lesions. The accumulation of tissue iron and ferritin also frequently occurs in CD163-positive and vessel-rich regions in the advanced atheroma. Although they were not always correspondingly positive on the serial sections, tissue iron and ferritin were significantly correlated. We conclude that erythrophagocytosis and hemoglobin catabolism by macrophages contribute to iron deposition and ferritin induction in human atheroma. The involvement of CD163 during ferritin induction may play an important role in modulating inflammatory processes in atherogenesis.

  • 33.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Jonasson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Apoptosis induced by oxidized low-density lipoprotein and 7beta-hydorxycholesterol in T cells and NK cells2006In: XIV International Symposium on Atherosclerosis,2006, 2006Conference paper (Other academic)
  • 34.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Jonasson, Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Cardiology. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
    Natural killer cells in coronary artery disease - susceptibility to oxidized cholesterol2006In: VIII Svenska Kardiovaskulära Vårmötet,2006, 2006Conference paper (Other academic)
  • 35.
    Li, Wei
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Yuan, Xi Ming
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Olsson, Anders
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Uptake of Oxidized LDL by Macrophages Results in Partial Lysosomal Enzyme Inactivation and Relocation1998In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 18, no 2, p. 177-84Article in journal (Refereed)
    Abstract [en]

    The cytotoxicity of oxidized LDL (oxLDL) to several types of artery wall cells might contribute to atherosclerosis by causing cell death, presumably by both apoptosis and necrosis. After its uptake into macrophage lysosomes by receptor-mediated endocytosis, oxLDL is poorly degraded, resulting in ceroid-containing foam cells. We studied the influence of oxLDL on lysosomal enzyme activity and, in particular, on lysosomal membrane stability and the modulation of these cellular characteristics by HDL and vitamin E (vit-E). Unexposed cells and cells exposed to acetylated LDL (AcLDL) were used as controls. The lysosomal marker enzymes cathepsin L and N-acetyl-β-glucosaminidase (NAβGase) were biochemically assayed in J-774 cells after fractionation. Lysosomal integrity in living cells was assayed by the acridine orange (AO) relocation test. Cathepsin D was immunocytochemically demonstrated in J-774 cells and human monocyte-derived macrophages. We found that the total activities of NAβGase and cathepsin L were significantly decreased, whereas their relative cytosolic activities were enhanced, after oxLDL exposure. Labilization of the lysosomal membranes was further proven by decreased lysosomal AO uptake and relocation to the cytosol of cathepsin D, as estimated by light and electron microscopic immunocytochemistry. HDL and vit-E diminished the cytotoxicity of oxLDL by decreasing the lysosomal damage. The results indicate that endocytosed oxLDL not only partially inactivates lysosomal enzymes but also destabilizes the acidic vacuolar compartment, causing relocation of lysosomal enzymes to the cytosol. Exposure to AcLDL resulted in its uptake with enlargement of the lysosomal apparatus, but the stability of the lysosomal membranes was not changed.

  • 36.
    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.
    Increased expression and translocation of lysosomal cathepsins contribute to macrophage apoptosis in atherogenesis2004In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1030, p. 427-433Article in journal (Refereed)
    Abstract [en]

    It has been recently reported that atherosclerotic lesions in both humans and mice express several lysosomal proteases, including cathepsins B, D, L, and S, which may affect plaque development and stability. The mechanisms responsible for the extralysosomal expression of lysosomal cathepsins and the related atherogenic implications remain unknown. We rind that the lesion-dependent expression of cathepsins B and L is mainly in macrophage-infiltrated areas of human carotid atheroma. These enzymes appear in the cytoplasm and nuclei of apoptotic macrophages (normally confined to the lysosomal compartment) and in the extracellular areas. After exposure to oxidized low-density lipoprotein (oxLDL) or 7 beta-hydroxycholesterol (7 beta-OH), macrophages initially transform into foam cells and then undergo apoptotic cell death. The oxidized lipids induce lysosomal destabilization, with leakage to the cytosol of lysosomal enzymes (cathepsins B, D, and L), as detected by cytochemistry and immunocytochemistry. A remarkable increase in cathepsin D mRNA levels was observed after 7 beta-OH exposure. Like macrophages within atheroma, intralysosomal cathepsins B and L are translocated to the cytoplasm and nuclei of 7B-OH-exposed cells. Our results suggest that endocytosed oxLDL and oxysterols not only destabilize the acidic vacuolar compartment but also cause the upregulation and translocation of lysosomal cathepsins, which may act as cleaving enzymes during the apoptotic process. The increased macrophage apoptosis and nuclear and matrix degradation by lysosomal enzymes in atheroma may play important roles in plaque development and rupture.

  • 37.
    Li, Wei
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    OxLDL-induced macrophage cytotoxicity is mediated by lysosomal rupture and modified by intralysosomal redox-active iron1998In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 29, no 5, p. 389-98Article in journal (Refereed)
    Abstract [en]

    Oxidized low density lipoprotein (oxLDL) is believed to play a central role in atherogenesis. LDL is oxidized in the arterial intima by mechanisms that are still only partially understood. OxLDL is then taken up by macrophages through scavenger receptor-mediated endocytosis, which then leads to cellular damage, including apoptosis. The complex mechanisms by which oxLDL induces cell injury are mostly unknown. This study has demonstrated that oxLDL-induced damage of macrophages is associated with iron-mediated intralysosomal oxidative reactions, which cause partial lysosomal rupture and ensuing apoptosis. This series of events can be prevented by pre-exposing cells to the iron-chelator, desferrioxamine (DFO), whereas it is augmented by pretreating the cells with a low molecular weight iron complex. Since both DFO and the iron complex would be taken up by endocytosis, and thus directed to the lysosomal compartment, the results suggest that the normal contents of lysosomal low molecular weight iron may play an important role in oxLDL-induced cell damage, presumably by catalyzing intralysosomal fragmentation of lipid peroxides and the formation of toxic aldehydes and oxygen-centered radicals.

  • 38.
    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.

  • 39.
    Li, Wei
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Yuan, XiMing
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Nordgren, Gunnar
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Dalen, Helge
    Department of Pathology, The Gade Institute, University of Bergen, Bergen, Norway.
    Dubowchik, Gene M.
    Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, CT, USA.
    Firestone, Raymond A.
    Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Induction of cell death by the lysosomotropic detergent MSDH2000In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 470, no 1, p. 35-39Article in journal (Refereed)
    Abstract [en]

    Controlled lysosomal rupture was initiated in lysosome-rich, macrophage-like cells by the synthetic lysosomotropic detergent, O-methyl-serine dodecylamide hydrochloride (MSDH). When MSDH was applied at low concentrations, resulting in partial lysosomal rupture, activation of pro-caspase-3-like proteases and apoptosis followed after some hours. Early during apoptosis, but clearly secondary to lysosomal destabilization, the mitochondrial transmembrane potential declined. At high concentrations, MSDH caused extensive lysosomal rupture and necrosis. It is suggested that lysosomal proteases, if released to the cytosol, may cause apoptosis directly by pro-caspase activation and/or indirectly by mitochondrial attack with ensuing discharge of pro-apoptotic factors.

  • 40.
    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.

  • 41.
    Li, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    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 Neuroscience and Locomotion, Pathology.
    Hellsten, Anna
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery.
    Leanderson, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Occupational and Environmental Medicine. Östergötlands Läns Landsting, Pain and Occupational Centre, Occupational and Environmental Medicine 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 Care, Pharmacology.
    Eaton, John Wallace
    USA .
    Yuan, Xi Ming
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Cytocidal effects of atheromatous plaque components: the death zone revisited.2006In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 20, p. 2281-2290Article in journal (Refereed)
    Abstract [en]

       

  • 42.
    Liang, Wenzhao
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center. Jilin University, Peoples R China.
    Ward, Liam
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    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.
    Ljunggren, Stefan
    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.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Lindahl, Mats
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Yuan, Ximing
    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.
    Distinctive proteomic profiles among different regions of human carotid plaques in men and women2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 26231Article in journal (Refereed)
    Abstract [en]

    The heterogeneity of atherosclerotic tissue has limited comprehension in proteomic and metabolomic analyses. To elucidate the functional implications, and differences between genders, of atherosclerotic lesion formation we investigated protein profiles from different regions of human carotid atherosclerotic arteries; internal control, fatty streak, plaque shoulder, plaque centre, and fibrous cap. Proteomic analysis was performed using 2-DE with MALDI-TOF, with validation using nLC-MS/MS. Protein mapping of 2-DE identified 52 unique proteins, including 15 previously unmapped proteins, of which 41 proteins were confirmed by nLC-MS/MS analysis. Expression levels of 18 proteins were significantly altered in plaque regions compared to the internal control region. Nine proteins showed site-specific alterations, irrespective of gender, with clear associations to extracellular matrix remodelling. Five proteins display gender-specific alterations with 2-DE, with two alterations validated by nLC-MS/MS. Gender differences in ferritin light chain and transthyretin were validated using both techniques. Validation of immunohistochemistry confirmed significantly higher levels of ferritin in plaques from male patients. Proteomic analysis of different plaque regions has reduced the effects of plaque heterogeneity, and significant differences in protein expression are determined in specific regions and between genders. These proteomes have functional implications in plaque progression and are of importance in understanding gender differences in atherosclerosis.

  • 43.
    Messner, Karola
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Orthopaedics and Sports Medicine.
    Wei, Wei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Orthopaedics and Sports Medicine.
    Andersson, B.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Orthopaedics and Sports Medicine. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Gillquist, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Orthopaedics and Sports Medicine. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Räsänen, T.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Orthopaedics and Sports Medicine.
    Rat model of Achilles tendinitis1999In: Acta Anatomica, ISSN 0001-5180, E-ISSN 1421-9654, Vol. 165, p. 30-39Article in journal (Refereed)
  • 44.
    Miah, Sayem
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Zadeh, Shahram Nour Mohammad
    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. Östergötlands Läns Landsting, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Expression of Egr1 and p53 in human carotid plaques and apoptosis induced by 7-oxysterol or p53.2013In: Experimental and Toxicological Pathology, ISSN 0940-2993, E-ISSN 1618-1433, Vol. 65, no 5, p. 677-682Article in journal (Refereed)
    Abstract [en]

    Egr-1 and p53 are involved in pathology of both atherosclerosis and cancer. However, it is unknown whether p53 and Egr1 are interactively involved in apoptosis in atherosclerosis. We found that in human carotid plaques, the expression of p53 was inversely correlated with Egr1. In U937 cells, 7 beta-hydroxycholesterol and 7-ketocholesterol induced production of reactive oxygen species (ROS), transient up-regulation of Egr1 followed by late induction of p53 and apoptosis. Cells with nuclear fragmentation induced by 7-oxysterol or p53 showed increased levels of p53, but decreased levels of Egr1. In conclusion, ROS induced by 7-oxysterols may function as an early initiator of Egr1 expression. The late induced p53 by 7-oxysterols contributes to apoptotic cell death and is linked to the reduction of Egr1 levels, which resembles the differential expression of p53 and Egr1 in human atheroma progression.

  • 45.
    Persson, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Sauma, Lilian
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    Safholm, Annette
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Xu, Lihua
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    LDL and UV-oxidized LDL induce upregulation of iNOS and NO in unstimulated J774 macrophages and HUVEC2009In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 117, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Oxidized low-density lipoprotein (LDL) diminishes NO production from activated macrophages. The interaction between LDL and inactivated macrophages is neglected and controversial. This study examines the effect of LDL, 7-oxysterols and iron compounds on NO production in unstimulated J774 macrophages. J774 cells and human umbilical vein endothelial cells (HUVEC) were either incubated for 24 h with native LDL (LDL) or ultraviolet (UV)-oxidized LDL (UVoxLDL), in the absence or presence of an inducible nitric oxide synthase (iNOS)- or an endothelial constitutive nitric oxide synthase (eNOS)-inhibitor. J774 cells were also incubated with lipopolysaccharide (LPS), in the absence or presence of an iNOS- or an eNOS-inhibitor. Nitrite was analysed as a marker of NO production. The mRNA levels of iNOS were evaluated by reverse transcriptase polymerase chain reaction. LDL and UVoxLDL significantly increased NO production from unstimulated J774 macrophages. This increase in NO was accompanied by enhanced expression of iNOS mRNA, and was inhibited by the iNOS inhibitor. Furthermore, NO production was elevated and angiotensin-converting enzyme (ACE) activity was reduced in HUVEC following the exposure to LDL and UVoxLDL. In conclusion, LDL may serve as an important inflammatory activator of macrophages and HUVEC, inducing inducible nitric oxide production but diminishing ACE. After its oxidation, this function of LDL may be further enhanced and may contribute to the regulation and progression of atheroma formation.

  • 46.
    Szymanowski, Aleksander
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Lundberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Evaldsson, Chamilly
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Nilsson, Lennart
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Backteman, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ernerudh, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Soluble Fas ligand is associated with natural killer cell dynamics in coronary artery disease2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 233, no 2, p. 616-622Article in journal (Refereed)
    Abstract [en]

    Objective: Apoptosis of natural killer (NK) cells is increased in patients with coronary artery disease (CAD) and may explain why NK cell levels are altered in these patients. Soluble forms of Fas and Fas ligand (L) are considered as markers of apoptosis. Here, we investigated whether plasma levels of Fas and FasL were associated with NK cell apoptosis and NK cell levels in CAD patients. Methods: Fas and FasL in plasma were determined by ELISA in 2 cohorts of CAD patients; one longitudinal study measuring circulating NK cells and apoptotic NK cells by flow cytometry 1 day, 3 months and 12 months after a coronary event and one cross-sectional study measuring NK cell apoptosis ex vivo. Both studies included matched healthy controls. Fas and FasL were also determined in supernatants from NK cells undergoing cytokine-induced apoptosis in cell culture. Results: In the 12-month longitudinal study, plasma FasL increased by 15% (p less than 0.001) and NK cell levels by 31% (p less than 0.05) while plasma Fas did not change. Plasma FasL and NK cell levels were significantly related at 3 months and 12 months, r = 0.40, p less than 0.01. Furthermore, plasma FasL, but not plasma Fas, correlated with NK cell apoptosis ex vivo in CAD patients, r = 0.54, p less than 0.05. In vitro, cytokine-induced apoptosis of NK cells resulted in abundant release of FasL. Conclusion: In CAD patients, FasL in plasma is associated with both apoptotic susceptibility of NK cells and dynamic changes in circulating NK cells. NK cells are also themselves a potential source of soluble FasL. Our findings link NK cell status to a soluble marker with possible atheroprotective effects thereby supporting a beneficial role of NK cells in CAD.

  • 47.
    Ward, Liam
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Olausson, Patrik
    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.
    Li, Wei
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Yuan, Ximing
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Proteomics and multivariate modelling reveal sex-specific alterations in distinct regions of human carotid atheroma2018In: Biology of Sex Differences, ISSN 2042-6410, Vol. 9, article id 54Article in journal (Refereed)
    Abstract [en]

    BackgroundAtherosclerotic lesions are comprised of distinct regions with different proteomic profiles. Men and women develop differences in lesion phenotype, with lesions from women generally being more stable and less prone to rupture. We aimed to investigate the differences in proteomic profiles between sexes, including distinct lesion regions, to identify altered proteins that contribute to these differences observed clinically.MethodsCarotid endarterectomy samples (ten men/ten women) were obtained, and intraplaque biopsies from three distinct regions (internal control, fatty streak and plaque) were analysed by tandem-mass spectrometry. Multivariate statistical modelling, using orthogonal partial least square-discriminant analysis, was used to discriminate the proteomes between men and women.ResultsMultivariate discriminant modelling revealed proteins from 16 functional groups that displayed sex-specific associations. Additional statistics revealed ten proteins that display region-specific alterations when comparing sexes, including proteins related to inflammatory response, response to reactive oxygen species, complement activation, transport and blood coagulation. Transport protein afamin and blood coagulation proteins antithrombin-III and coagulation factor XII were significantly increased in plaque region from women. Inflammatory response proteins lysozyme C and phospholipase A2 membrane-associated were significantly increased in plaque region from men. Limitations with this study are the small sample size, limited patient information and lack of complementary histology to control for cell type differences between sexes.ConclusionsThis pilot study, for the first time, utilises a multivariate proteomic approach to investigate sexual dimorphism in human atherosclerotic tissue, and provides an essential proteomic platform for further investigations to help understand sexual dimorphism and plaque vulnerability in atherosclerosis.

  • 48.
    Wei, Wei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Orthopaedics and Sports Medicine.
    Messner, Karola
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Orthopaedics and Sports Medicine.
    Maturation-dependent durability of spontaneous cartilage repair in rabbit knee joint.1999In: Journal of Biomedical Materials Research, ISSN 0021-9304, E-ISSN 1097-4636, Vol. 46, p. 539-548Article in journal (Refereed)
  • 49.
    Yu, Zhengquan
    et al.
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Department of Neuroscience and Locomotion, Neurosurgery. Linköping University, Faculty of Health Sciences.
    Li, Wei
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Brunk, Ulf
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    3-Aminopropanal is a lysosomotropic aldehyde that causes oxidative stress and apoptosis by rupturing lysosomes2003In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 111, no 6, p. 643-652Article in journal (Refereed)
    Abstract [en]

    During cerebral ischemia and following trauma, potent cytotoxic polyamine-derived aminoaldehydes form, diffuse, and damage adjacent tissues not directly subjected to the initial insult. One such aldehyde is 3-aminopropanal (3-AP). The mechanisms by which such a small aldehydic compound is excessively cytotoxic have been unclear until recently when we showed that 3-AP, having the structure of a weak lysosomotropic base, concentrates within the acidic vacuolar compartment and causes lysosomal rupture that, in turn, induces caspase activation and apoptotic cell death. Here, using cultured J774 cells and 3-AP as a way to selectively burst lysosomes, we show that moderate lysosomal rupture induces a transient wave of oxidative stress. The start of this oxidative stress period is concomitant with a short period of enhanced mitochondrial membrane potential that later fades and is replaced by a decreased potential before the oxidative stress diminishes. The result of the study suggests that oxidative stress, which has often been described during apoptosis induced by agonists other than oxidative stress per se, may be a consequence of lysosomal rupture with direct and/or indirect effects on mitochondrial respiration and electron transport causing a period of passing enhanced formation of reactive oxygen species.

  • 50.
    Yuan, Xi Ming
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Li, Wei
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Baird, Sarah K
    Carlsson, Maria
    Melefors, Öjar
    Secretion of ferritin by iron-laden macrophages and influence of lipoproteins2004In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 38, no 10, p. 1133-1142Article in journal (Refereed)
    Abstract [en]

    Increasing evidence supports a role of cellular iron in the initiation and development of atherosclerosis. We and others reported earlier that iron-laden macrophages are associated with LDL oxidation, angiogenesis, nitric oxide production and apoptosis in atherosclerotic processes. Here we have further studied perturbed iron metabolism in macrophages, their interaction with lipoproteins and the origin of iron accumulation in human atheroma. In both early and advanced human atheroma lesions, hemoglobin and ferritin accumulation correlated with the macrophage-rich areas. Iron uptake into macrophages, via transferrin receptors or scavenger receptor-mediated erythrophagocytosis, increased cellular iron and accelerated ferritin synthesis at both mRNA and protein levels. The binding activity of iron regulatory proteins was enhanced by desferrioxamine (DFO) and decreased by hemin and iron compounds. Iron-laden macrophages exocytosed both iron and ferritin into the culture medium. Exposure to oxidized low-density lipoprotein (oxLDL, ≥50 μg/ml,) resulted in <20% apoptosis of iron-laden human macrophages, but cells remained impermeable after a 24 h period and an increased excretion of ferritin could be observed by immunostaining techniques. Exposure to high-density lipoprotein (HDL) significantly decreased ferritin excretion from these cells. We conclude: (i) erythrophagocytosis and hemoglobin catabolism by macrophages contribute to ferritin accumulation in human atherosclerotic lesions and, (ii) iron uptake into macrophages leads to increased synthesis and secretion of ferritin, (iii) oxidized LDL and HDL have different effects on these processes.

12 1 - 50 of 59
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf