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  • 1.
    Alehagen, Urban
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Ljungberg, Liza
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Gender difference in adiponectin associated with cardiovascular mortality2015In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 16, no 9Article in journal (Refereed)
    Abstract [en]

    Background: It is important to identify cardiovascular diseases in patients at high risk. To include genetics into routine cardiological patients has therefore been discussed recently. We wanted to evaluate the association between high-molecular weight adiponectin and cardiovascular risk, and secondly in the same population evaluate if specific genotype differences regarding risk could be observed, and thirdly if gender differences could be seen. Method: Four hundred seventy-six elderly participants recruited from a rural community were included. All participants underwent a clinical examination, echocardiography, and blood sampling and the single nucleotide polymorphism (SNP) (rs266729) of adiponectin was analysed. Follow-up time was 6.7 years. Results: Those with high serum concentration of adiponectin had a more 2 fold increased cardiovascular risk, and it might be that females exhibits even higher risk where a more than 5 fold increased risk could be seen. The result could be demonstrated even in a multivariate model adjusting for well-known clinical risk factors. However, as the sample size was small the gender differences should be interpreted with caution. In the genotype evaluation the C/C carriers of the female group had a more than 9-fold increased risk of cardiovascular mortality, however the confidence interval was wide. Such genotype difference could not be found in the male group. Conclusion: High level of adiponectin was associated with increased cardiovascular risk. Also a gender difference in the genotype evaluation could be seen where the C/C carriers obtained higher risk in the female group but not in the male group. Thus, in order to identify patients at risk early, genetic analyses may add to the armamentarium used in the clinical routine. However, information should be regarded as hypothesis generating as the sample size was small and should stimulate further research in individualized cardiovascular prevention and treatment.

  • 2.
    Alehagen, Urban
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Uppsala Univ, Sweden.
    Gender difference and genetic variance in lipoprotein receptor-related protein 1 is associated with mortality2019In: BIOMEDICAL REPORTS, ISSN 2049-9434, Vol. 11, no 1Article in journal (Refereed)
    Abstract [en]

    Cardiovascular diseases are an important health resource problem and studies have shown a genetic association between single nucleotide polymorphisms (SNPs) and cardiovascular diseases. According to the literature, lipoprotein receptor-related protein 1 (LRP1) is associated with coronary artery disease. The aim of the present study was to evaluate a possible association between different genotypes of LRP1 and all-cause and cardiovascular mortality from a gender perspective. In the present study, 489 elderly community-living people were invited to participate. Clinical examination, echocardiography and blood sampling including SNP analyses of LRP1 (rs1466535) were performed, including the T/T, C/T and C/C genotypes, and the participants were followed for 6.7 years. During the follow-up period, 116 (24%) all-cause and 75 (15%) cardiovascular deaths were registered. In the female population, the LRP1 of the T/T or C/T genotype exhibited a 5.6-fold increased risk of cardiovascular mortality and a 2.8-fold increased risk of all-cause mortality compared with the C/C genotype. No such genotype differences could be seen in the male population. Gender differences could be seen regarding the risk of mortality in the different genotypes. Females with the LRP1 T/T or C/T genotypes exhibited a significantly increased risk of both all-cause and cardiovascular mortality compared with the C/C genotypes. Therefore, more individualized cardiovascular prevention and treatment should be prioritized. However, since this was a small study, the observations should only be regarded as hypothesis-generating.

  • 3.
    Bertorello, Alejandro M.
    et al.
    Karolinska Institute, Sweden.
    Pires, Nuno
    Bial Portela and Ca SA, Portugal.
    Igreja, Bruno
    Bial Portela and Ca SA, Portugal.
    Joao Pinho, Maria
    University of Porto, Portugal.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden.
    Wikstrom, Johannes
    AstraZeneca RandD, Sweden.
    Behrendt, Margareta
    AstraZeneca RandD, Sweden.
    Hamsten, Anders
    Karolinska Institute, Sweden.
    Eriksson, Per
    Karolinska Institute, Sweden.
    Soares-da-Silva, Patricio
    Bial Portela and Ca SA, Portugal; University of Porto, Portugal.
    Brion, Laura
    Karolinska Institute, Sweden.
    Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)2015In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 116, no 4, p. 642-U190Article in journal (Refereed)
    Abstract [en]

    Rationale: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-beta 1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1+/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-beta 1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-beta 1-signaling inhibition.

  • 4.
    Di Gennaro, Antonio
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden.
    Mäyranpää, Mikko
    Wihuri Research Institute, Helsinki, Finland; University of Helsinki, Finland .
    Gabrielsen, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Swedenborg, Jesper
    Karolinska University Hospital, Stockholm, Sweden .
    Hamsten, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Samuelsson, Bengt
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institutet, Stockholm, Sweden.
    Häggström, Jesper
    Karolinska Institutet, Stockholm, Sweden.
    Increased expression of leukotriene C-4 synthase and predominant formation of cysteinyl-leukotrienes in human abdominal aortic aneurysm2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 49, p. 21093-21097Article in journal (Refereed)
    Abstract [en]

    Leukotrienes (LTs) are arachidonic acid-derived lipid mediators involved in the pathogenesis and progression of diverse inflammatory disorders. The cysteinyl-leukotrienes LTC4, LTD4, and LTE4 are important mediators of asthma, and LTB4 has recently been implicated in atherosclerosis. Here we report that mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase (5-LO), 5-LO-activating protein (FLAP), and LTC4 synthase (LTC4S), are significantly increased in the wall of human abdominal aortic aneurysms (AAAs). In contrast, mRNA levels of LTA(4) hydrolase, the enzyme responsible for the biosynthesis of LTB4, are not increased. Immunohistochemical staining of AAA wall revealed focal expression of 5-LO, FLAP, and LTC4S proteins in the media and adventitia, localized in areas rich in inflammatory cells, including macrophages, neutrophils, and mast cells. Human AAA wall tissue converts arachidonic acid and the unstable epoxide LTA(4) into significant amounts of cysteinyl-leukotrienes and to a lesser extent LTB4. Furthermore, challenge of AAA wall tissue with exogenous LTD4 increases the release of matrix metalloproteinase (MMP) 2 and 9, and selective inhibition of the CysLT1 receptor by montelukast blocks this effect. The increased expression of LTC4S, together with the predominant formation of cysteinyl-leukotrienes and effects on MMPs production, suggests a mechanism by which LTs may promote matrix degradation in the AAA wall and identify the components of the cysteinyl-leukotriene pathway as potential targets for prevention and treatment of AAA.

  • 5.
    Dimberg, Jan
    et al.
    University College of Health Sciences, Jönköping, Sweden.
    Dienus, Olaf
    Ryhov County Hospital, Jönköping, Sweden.
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Wågsäter, Dick
    Karolinska Institute, Stockholm, Sweden.
    Expression and gene polymorphisms of the chemokine CXCL5 in colorectal cancer patients2007In: International Journal of Oncology, ISSN 1019-6439, Vol. 31, no 1, p. 97-102Article in journal (Refereed)
    Abstract [en]

    Several studies indicate that chemokines play important roles in colorectal mucosal immunity by recruiting leukocytes into and out of the lamina propria adjacent to the epithelium. The chemokine CXCL5 which is expressed by epithelial cells within colorectal mucosa is a chemoattractant for neutrophils and has been implicated in Crohns disease and ulcerative colitis. In addition, CXCL5 is one chemokine which promote angiogenesis related to cancer. The objective of this study was to determine by ELISA assay whether CXCL5 protein level is altered in colorectal cancer (CRC) tissues (n=80) compared with paired normal mucosa. Furthermore, the plasma CXCL5 levels from CRC patients (n=62) compared with controls (n=71) were also examined. Using a TaqMan system we screened for -156G -greater than C and +398G -greater than A CXCL5 gene variants in CRC patients (n=228) and a control group (n=231) to assess the role of CXCL5 genotype in CRC. The analyses showed that CXCL5 protein level in colorectal tumours was significantly (P less than 0.0001) higher than in normal tissue and was lower in plasma in CRC patients compared with controls (P=0.026). Immunohistochemistry revealed CXCL5 immunoreactivity mainly in epithelial cells of the colorectal carcinoma and in normal epithelial cells. Furthermore, patients who were -156C carriers had higher CXCL5 protein concentration compared with -156G carriers in normal tissue (P=0.027) and CXCL5 protein levels in cancerous tissue tended to be higher for the patient -156C carriers (P=0.059). To our knowledge this is the first report on the influence of CXCL5 gene variants and their relation to expression of CXCL5 protein in human CRC.

  • 6.
    Dimberg, Jan
    et al.
    University College of Health Sciences, Jönköping, Sweden.
    Dienus, Olaf
    Ryhov County Hospital, Jönköping, Sweden .
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden .
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden .
    Wågsäter, Dick
    Karolinska Institute, Stockholm, Sweden .
    Polymorphisms of Fractalkine receptor CX3CR1 and plasma levels of its ligand CX3CL1 in colorectal cancer patients2007In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 22, no 10, p. 1195-1200Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS:

    The chemokine Fractalkine/CX3CL1, which is expressed by epithelial cells within normal colorectal mucosa and in colorectal cancer (CRC), is thought to have a crucial role in colorectal mucosal immunity by recruiting leucocytes via the receptor CX3CR1. The purpose of this study was to investigate two single-nucleotide polymorphisms of the Fractalkine receptor/CX3CR1 gene, V249I and T280M, in CRC to find out whether they occur more often in patients with CRC than in non-CRC individuals. In the search for tumour markers, we also intended to determine whether plasma levels of Fractalkine were correlated with parameters such as Dukes' stage, tumour localisation, gender and age in CRC patients.

    MATERIALS AND METHODS:

    Genomic deoxyribonucleic acid from 223 CRC patients and 229 controls was amplified by polymerase chain reaction, and the polymorphisms were detected by the restriction fragment length polymorphism analysis. Fractalkine/CX3CL1 was analysed in plasma from 62 CRC patients and 78 controls using enzyme-linked immunosorbent assay.

    RESULTS:

    The variant V249I was significantly different in genotype and allelic distribution between CRC patients and control subjects, P = 0.028 and P = 0.048, respectively. We also found that individuals with the I249 allele in homozygote state were less frequent in the CRC group (3.1%) compared with controls (9.2%; P = 0.008). No significant difference was observed regarding Fractalkine/CX3CL1 levels in plasma between patients and the control group.

    CONCLUSION:

    Our results suggest that the lack of the allele I249 of the CX3CR1 gene may play a partial or minor role in CRC and that plasma Fractalkine/CX3CL1 does not seem to be a useful tumour marker that reflects the disease outcome of CRC.

  • 7.
    Dimberg, Jan
    et al.
    University College of Health Sciences, Jönköping, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden; .
    Wågsäter, Dick
    Karolinska Institute, Stockholm, Sweden.
    Polymorphism and circulating levels of the chemokine CXCL12 in colorectal cancer patients2007In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 19, no 1, p. 11-15Article in journal (Refereed)
    Abstract [en]

    The chemokine CXCL12, also known as stromal cell-derived factor-1 (SDF-1), is a small protein that regulates leukocyte trafficking and is variably expressed in a number of normal and cancer tissues. CXCL12 as ligand and its receptor CXCR4 have been implicated in colorectal cancer (CRC) progression including angiogenesis and metastasis. A CXCL12 gene variant CXCL12-A (CXCL12-G801A, a single nucleotide polymorphism in the 3 untranslated region) is associated with increased susceptibility to breast cancer. Based on the suggested role of CXCL12 in the pathogenesis of cancer we examined the association of the gene variant CXCL12-A with CRC. The polymorphism was analysed with PCR and RFLP methods. Furthermore, the plasma CXCL12 levels from patients with CRC were also examined. There was no significant difference in genotype distribution and allelic frequencies between CRC patients (n=151) and controls (n=141). On the other hand, we found that the carrying rate of allele CXCL12-A was higher in colon cancer patients compared with rectal cancer patients (P=0.017). Analyses by ELISA showed that CRC patients (n=63) had a lower CXCL12 plasma level compared with controls (P less than 0.0001). Moreover, patients with tumours classified as Dukes stage B and C revealed lower levels than patients with tumours in Dukes stage A. Further studies with larger samples of patients are necessary to determine whether the CXCL 12 polymorphism and plasma level reflect the clinical outcome of CRC and have an impact on CRC progression.

  • 8.
    Dimberg, Jan
    et al.
    University College of Health Sciences, Jönköping, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Wågsäter, Dick
    Karolinska Institute, Stockholm, Sweden.
    Expression of CD137 and CD137 ligand in colorectal cancer patients2006In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 15, no 5, p. 1197-1200Article in journal (Refereed)
    Abstract [en]

    The cytokine CD137, a member of the TNF receptor family, is expressed by T cells and regulates activation and proliferation of these cells. The CD137 ligand (CD137L) is expressed by antigen-presenting cells including macrophages, but also on various carcinoma cells. CD137/CD137L interaction plays a central role in sustaining T cell and macrophage activation, i.e. in antitumour immunity. The present study was designed to investigate whether CD137 and CD137L protein levels are altered in colorectal tumours compared with paired normal tissues. The CD137 and CD137L plasma levels from patients with colorectal cancer were also examined. Collectively, we noted a significantly lower CD137L level in cancerous tissue compared with paired normal tissue, and the difference in CD137L protein level was significantly lower in the colon cancer subgroup compared with paired normal colon tissue. On the other hand, we found an elevated CD137 protein level in the rectal cancer subgroup compared with paired normal rectal tissue. Patients with a tumour localised in the colon revealed significantly higher soluble CD137 protein concentration in the plasma than patients with a tumour localised in the rectum, and there was a tendency toward a higher concentration of CD137L protein in the plasma from patients with tumour localised in the colon. Moreover, the plasma concentrations of CD137 and CD137L proteins were strongly and significantly correlated. The different expression levels of CD137 and CD137L in the colon and rectum may reflect divergent mechanisms involved in the pathogenesis of colorectal cancer and lead to dissimilar protective immunity.

  • 9.
    Dimberg, Jan
    et al.
    University College of Health Sciences, Jönköping, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Wågsäter, Dick
    University of Örebro, Sweden.
    Protein expression of the chemokine, CCL28, in human colorectal cancer2006In: International Journal of Oncology, ISSN 1019-6439, Vol. 28, no 2, p. 315-319Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence points out that chemokines play important roles in colorectal mucosal immunity by recruiting leukocytes into and out of the lamina propria adjacent to the epithelium. The chemokine, CCL28, which is expressed by epithelial cells within colorectal mucosa is thought to have dual roles as a chemoattractant for leukocytes expressing CCR10 and/or CCR3 and a mediator of antimicrobial activity. To date, there is little known about the presence of CCL28 in colorectal cancer. The objective of this study was to determine whether the CCL28 protein level is altered in colorectal tumours (n=76) compared with paired normal mucosa. Further, the plasma CCL28 levels from patients with colon and rectal cancer were also examined. Immunohistochemistry revealed heterogeneous CCL28 protein expression in tumour and normal epithelial cells. Analyses by ELISA showed that the CCL28 protein level in colon tumours was significantly (P less than 0.001) lower than in normal tissue and that the difference in CCL28 protein level between rectal tumour and normal tissue was not significant. Patients with a tumour localized in the colon had significantly (P less than 0.05) higher plasma CCL28 protein levels than patients with a tumour localized in the rectum. These discrepancies may suggest that there are different mechanisms and signalling pathways involved in the pathogenesis of cancer in the colon and rectum and thereby differentially promote the expression and secretion of CCL28 protein. Further studies on CCL28 protein in colorectal cancer with an extended number of patients are necessary to conclude whether tissue levels and plasma concentrations carry significant clinical relevance.

  • 10.
    Folkersen, Lasse
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden.
    Paloschi, Valentina
    Karolinska Institutet, Stockholm, Sweden.
    Jackson, Veronica
    Karolinska Institutet, Stockholm, Sweden.
    Petrini, Johan
    Karolinska Institutet, Stockholm, Sweden.
    Kurtovic, Sanela
    Karolinska Institutet, Stockholm, Sweden.
    Maleki, Shohreh
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Maria J.
    Karolinska Institutet, Stockholm, Sweden.
    Caidahl, Kenneth
    Karolinska Institutet, Stockholm, Sweden.
    Hamsten, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Michel, Jean-Baptiste
    INSERM U698, Paris, France.
    Liska, Jan
    Karolinska Institutet, Stockholm, Sweden.
    Gabrielsen, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Franco-Cereceda, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institutet, Stockholm, Sweden.
    Unraveling Divergent Gene Expression Profiles in Bicuspid and Tricuspid Aortic Valve Patients with Thoracic Aortic Dilatation: The ASAP Study2011In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 17, no 11-12, p. 1365-1373Article in journal (Refereed)
    Abstract [en]

    Thoracic aortic aneurysm (TAA) is a common complication in patients with a bicuspid aortic valve (BAV), the most frequent congenital heart disorder. For unknown reasons TAA occurs at a younger age, with a higher frequency in BAV patients than in patients with a tricuspid aortic valve (TAV), resulting in an increased risk for aortic dissection and rupture. To investigate the increased TAA incidence in BAV patients, we obtained tissue biopsy samples from nondilated and dilated aortas of 131 BAV and TAV patients. Global gene expression profiles were analyzed from controls and from aortic intima-media and adventitia of patients (in total 345 samples). Of the genes found to be differentially expressed with dilation, only a few (less than4%) were differentially expressed in both BAV and TAV patients. With the use of gene set enrichment analysis, the cell adhesion and extracellular region gene ontology sets were identified as common features of TAA in both BAV and TAV patients. Immune response genes were observed to be particularly overexpressed in the aortic media of dilated TAV samples. The divergent gene expression profiles indicate that there are fundamental differences in TAA etiology in BAV and TAV patients. Immune response activation solely in the aortic media of TAV patients suggests that inflammation is involved in TAA formation in TAV but not in BAV patients. Conversely, genes were identified that were only differentially expressed with dilation in BAV patients. The result has bearing on future clinical studies in which separate analysis of BAV and TAV patients is recommended.

  • 11.
    Folkesson, Maggie
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Li, Chunjun
    Tianjin Medical University, Peoples R China; Tianjin Medical University, Peoples R China.
    Frebelius, Siw
    Karolinska Institute, Sweden.
    Swedenborg, Jesper
    Karolinska Institute, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Jon Williams, Kevin
    Temple University, PA 19122 USA; University of Gothenburg, Sweden.
    Eriksson, Per
    Karolinska Institute, Sweden.
    Roy, Joy
    Karolinska Institute, Sweden.
    Liu, Ming-Lin
    Temple University, PA 19122 USA; University of Penn, PA 19104 USA; Philadelphia Vet Affairs Medical Centre, PA USA.
    Proteolytically active ADAM10 and ADAM17 carried on membrane microvesicles in human abdominal aortic aneurysms2015In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 114, no 6, p. 1165-1174Article in journal (Refereed)
    Abstract [en]

    The intraluminal thrombus (ILT) of human abdominal aortic aneurysm (AAA) has been suggested to damage the underlying aortic wall, but previous work found scant activity of soluble proteases in the abluminal layer of the ILT, adjacent to the aneurysm. We hypothesised that transmembrane proteases carried by membrane microvesicles (MV) from dying cells remain active in the abluminal ILT. ILTs and AAA segments collected from 21 patients during surgical repair were assayed for two major transmembrane proteases, ADAM10 (a disintegrin and metalloprotease-10) and ADAM17. We also exposed cultured cells to tobacco smoke and assessed ADAM10 and ADAM17 expression and release on MVs. Immunohistochemistry showed abundant ADAM10 and ADAM17 protein in the ILT and underlying aneurysmal aorta. Domain-specific antibodies indicated both transmembrane and shed ADAM17. Importantly, ADAM10 and ADAM 17 in the abluminal ILT were enzymatically active. Electron microscopy of abluminal ILT and aortic wall showed MVs with ADAM10 and ADAM17. By flow cytometry, ADAM-positive microvesicles from abluminal ILT carried the neutrophil marker CD66, but not the platelet marker CD61. Cultured HL60 neutrophils exposed to tobacco smoke extract showed increased ADAM10 and ADAM17 content, cleavage of these molecules into active forms, and release of MVs carrying mature ADAM10 and detectable ADAM17. In conclusion, our results implicate persistent, enzymatically active ADAMs on MVs in the abluminal ILT, adjacent to the aneurysmal wall. The production of ADAM10- and ADAM17-positive MVs from smoke-exposed neutrophils provides a novel molecular mechanism for the vastly accelerated risk of AAA in smokers.

  • 12.
    Folkesson, Maggie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Sadowska, Natalia
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Carlhäll, Carl-Johan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models2016In: Biology Open, ISSN 2046-6390, Vol. 5, no 7, p. 970-978Article in journal (Refereed)
    Abstract [en]

    Tobacco use is strongly associated with cardiovascular disease and the only avoidable risk factor associated with development of aortic aneurysm. While smoking is the most common form of tobacco use, snuff and other oral tobacco products are gaining popularity, but research on potentially toxic effects of oral tobacco use has not kept pace with the increase in its use. Here, we demonstrate that cigarette smoke and snuff extracts are highly toxic to developing zebrafish embryos. Exposure to such extracts led to a palette of toxic effects including early embryonic mortality, developmental delay, cerebral hemorrhages, defects in lymphatics development and ventricular function, and aneurysm development. Both cigarette smoke and snuff were more toxic than pure nicotine, indicating that other compounds in these products are also associated with toxicity. While some toxicities were found following exposure to both types of tobacco product, other toxicities, including developmental delay and aneurysm development, were specifically observed in the snuff extract group, whereas cerebral hemorrhages were only found in the group exposed to cigarette smoke extract. These findings deepen our understanding of the pathogenic effects of cigarette smoking and snuff use on the cardiovascular system and illustrate the benefits of using zebrafish to study mechanisms involved in aneurysm development.

  • 13.
    Folkesson, Maggie
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Gulbins, Erich
    University of Duisburg-Essen, University of Cincinnati.
    Japtok, Lukasz
    The department of Toxicology, Institute of Nutritional Science, University of Potsdam.
    Kleuser, Burkhard
    The department of Toxicology, Institute of Nutritional Science, University of Potsdam.
    Welander, Martin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms2017In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 65, no 4, p. 1171-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study.

    METHODS AND RESULTS: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT.

    CONCLUSIONS: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage.

  • 14.
    Gacic, Jelena
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Slind Olsen, Renate
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. County Hospital Ryhov, Sweden.
    Söderberg, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Gustafsson, Therese
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Geffers, Robert
    Helmholtz Centre Infect Research, Germany.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Matussek, Andreas
    County Hospital Ryhov, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Imatinib reduces cholesterol uptake and matrix metalloproteinase activity in human THP-1 macrophages2016In: Pharmacological Reports, ISSN 1734-1140, E-ISSN 2299-5684, Vol. 68, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    Background: Imatinib mesylate (Glivec, formerly STI-571) is a selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. However, there are reports suggesting that imatinib could be atheroprotective by lowering plasma low-density lipoprotein (LDL). Aim: To investigate the potential inhibitory effect of imatinib on cholesterol uptake in human macrophages as well as its effect on matrix metalloproteinase (MMP) activity. Methods and results: Uptake of fluorescence-labeled LDL was analyzed using flow cytometry. Macrophages treated with imatinib showed a 23.5%, 27%, and 15% decrease in uptake of native LDL (p < 0.05), acetylated LDL (p < 0.01), and copper-modified oxidized LDL (p < 0.01), respectively. Gel based zymography showed that secretion and activity of MMP-2 and MMP-9 were inhibited by imatinib. Using GeneChip Whole Transcript Expression array analysis, no obvious gene candidates involved in the mechanisms of cholesterol metabolism or MMP regulation were found to be affected by imatinib. Instead, we found that imatinib up-regulated microRNA 155 (miR155) by 43.8% and down-regulated ADAM metallopeptidase domain 28 (ADAM28) by 41.4%. Both genes could potentially play an atheroprotective role and would be interesting targets in future studies. Conclusion: Our results indicate that imatinib causes post-translational inhibition with respect to cholesterol uptake and regulation of MMP-2 and MMP-9. More research is needed to further evaluate the role of imatinib in the regulation of other genes and processes. (c) 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Sp. z o.o. All rights reserved.

  • 15.
    Jackson, Veronica
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Olsson, Therese
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Kurtovic, Sanela
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Folkersen, Lasse
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Paloschi, Valentina
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Franco-Cereceda, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Matrix metalloproteinase 14 and 19 expression is associated with thoracic aortic aneurysms2012In: Journal of Thoracic and Cardiovascular Surgery, ISSN 0022-5223, E-ISSN 1097-685X, Vol. 144, no 2, p. 459-466Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    It is hypothesized that an altered turnover of extracellular matrix mediated by matrix metalloproteinases (MMPs) is present in thoracic aortic aneurysms. Here, we analyzed the occurrence of MMPs and MMP inhibitors in ascending aortic aneurysms in patients with bicuspid and tricuspid aortic valves.

    METHODS:

    Expression of 23 MMPs and their inhibitors was measured in aortic intima/media and adventitia in 109 patients (40 tricuspid, 69 bicuspid, 68 with aortic diameter≥4.5 cm, and 41 with ≤4.0 cm) using Affymetrix Exon arrays (Affymetrix, Santa Clara, Calif). Gene expression was confirmed by quantitative real-time polymerase chain reaction. Principal components analysis was used to study differences in gene expression. Immunohistochemistry was used to study protein expression.

    RESULTS:

    We detected messenger RNA expression for gelatinases (MMP2 and MMP9), stromelysin 3 (MMP11), all membrane bound MMPs (MMP14, MMP15, MMP16, MMP17, MMP24, MMP25), MMP19, MMP21, and MMP28 in ascending aorta. No expression of collagenases was detected. Principal components analysis showed that changes in mRNA expression between dilated and nondilated aorta were mainly detected in patients with tricuspid aortic valves. MMP14 and MMP19 showed higher expression in dilated aortas and MMP19 expression correlated positively to maximal aortic diameter in patients with tricuspid aortic valves (Rho=0.61, P=.004, and Rho=0.57, P=.008, using raw and body surface area-corrected aortic diameter, respectively). Immunohistochemical staining demonstrated increased medial expression of MMP14 and MMP19 in dilated aorta.

    CONCLUSIONS:

    The present study identifies MMP14 and MMP19 as proteolytic enzymes potentially involved in aneurysm formation in the ascending aorta of patients with tricuspid aortic valves

  • 16.
    Jatta, K.
    et al.
    University of Örebro, Sweden .
    Wågsäter, Dick
    University of Örebro, Sweden .
    Norgren, L.
    Örebro University Hospital, Sweden.
    Stenberg, B.
    Örebro University Hospital, Sweden.
    Sirsjö, A.
    University of Örebro, Sweden .
    Lipopolysaccharide-induced cytokine and chemokine expression in human carotid lesions2005In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 42, no 3, p. 266-271Article in journal (Refereed)
    Abstract [en]

    The release of cytokines and chemokines from activated immune-competent cells plays a crucial role in determining the pathology of the atherogenic progress. We investigated the effect of bacterial lipopolysaccharide (LPS) on cytokine/chemokine expression in carotid lesions and normal renal arteries. The lesions or renal arteries were incubated for 6 h at 37andDEG; C in serum-free media treated with or without LPS. After LPS treatment, increased protein levels of IL-1andbeta;, IL-6, IL-8, IL-10, TNF-andalpha; and MCP-1 were observed in the culture medium from the lesions measured with cytometric bead array. We were able to detect the induction of IL-1andbeta;, IL-6, IL-8, IL-10, TNF-andalpha; and MCP-1 mRNA in the lesions after stimulation with LPS using real-time PCR. In renal arteries, LPS also induces mRNA expression of all chemokines and cytokines investigated with the exception of IL-6. However, LPS induces significantly higher levels of TNF-andalpha;, IL-1andbeta; and IL-10 mRNA in lesions compared to renal arteries. The results suggest that infectious agents are capable of enhancing the production of cytokines/chemokines in an already ongoing inflammatory process such as in atherosclerosis, and that low levels of circulating LPS may affect the levels of pro-inflammatory cytokines much more in atherosclerotic vessels than in normal vessels and may contribute to the development of the atherosclerotic lesion. Copyright (C) 2005 S. Karger AG, Basel.

  • 17.
    Kolak, Maria
    et al.
    Karolinska Institutet, Stockholm, Sweden .
    Westerbacka, Jukka
    University of Helsinki, Finland .
    Velagapudi, Vidya
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden .
    Yetukuri, Laxman
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Makkonen, Janne
    University of Helsinki, Finland .
    Rissanen, Aila
    University of Helsinki, Finland .
    Häkkinen, Anna-Maija
    University of Helsinki, Finland .
    Lindell, Monica
    Karolinska Institutet, Stockholm, Sweden .
    Bergholm, Robert
    University of Helsinki, Finland .
    Hamsten, Anders
    Karolinska Institutet, Stockholm, Sweden .
    Eriksson, Per
    Karolinska Institutet, Stockholm, Sweden .
    Fisher, Rachel
    Karolinska Institutet, Stockholm, Sweden .
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland .
    Yki-Järvinen, Hannele
    Karolinska Institutet, Stockholm, Sweden .
    Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity2007In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 56, no 8, p. 1960-1968Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.

    RESEARCH DESIGN AND METHODS:

    A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.

    RESULTS:

    Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.

    CONCLUSIONS:

    Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.

  • 18.
    Mumtaz, Melad
    et al.
    Al-Nahrain University, Baghdad, Iraq .
    Wågsäter, Dick
    Karolinska Institute, Stockholm, Sweden .
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden .
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden .
    Zar, Niklas
    Ryhov County Hospital, Jönköping, Sweden .
    Dimberg, Jan
    University College of Health Sciences, Jönköping, Sweden .
    Decreased expression of the chemokine CCL21 in human colorectal adenocarcinomas2009In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 21, no 1, p. 153-158Article in journal (Refereed)
    Abstract [en]

    Recent studies have revealed participation of chemokines in cancer by regulating leukocyte movement to modify local immunoresponse. The chemokine CCL21 has been identified to play a pivotal role in homing and localization of immune cells to lymphoid tissue and into organ of non-lymphoid origin. In the cancer biology CCL21 seems to have multifaceted roles. CCL21 attracts CCR7 bearing cells especially T and dendritic cells but also various cancer cells. Besides the antitumour role as leukocyte recruiting, CCL21 has been shown to facilitate dendritic cell functions and to exert an angiostatic effect. To gain insight into the possible influence of CCL21 oil colorectal cancer (CRC) we determined whether the CCL21 is altered in CRC tissue. Collectively, by using ELISA we noted a significant lower CCL21 level in cancer tissue compared with paired normal tissue. Patients with a tumour localized in the rectum revealed significantly lower level of CCL21 than patients with a tumour localized in the colon both compared with paired normal tissue. We used immunohistochemistry and found heterogeneous immunoreactivity predominantly within areas of stromal cells mainly in macrophages. We also used a TaqMan system to investigate two single-nucleotide polymorphisms rs 11574915 and rs 2812377 with Supposed effect on CRC. No significant difference was observed between CRC and control subjects regarding genotype and allelic distributions or associations to clinical characteristics or CCL21 tissue levels. Our study implied that lower level of CCL21 in CRC tissue supports the idea that cancer is related to immunodeficiency probably depending on regulatory factors produced by tumour cells and that the different levels of CCL21 in rectum and colon may reflect divergent mechanisms in colorectal carcinogenesis. Further studies are needed to clarify whether the CCL21 level has an impact on CRC progression and survival rate.

  • 19.
    Mälarstig, A.
    et al.
    Karolinska University Hospital, Stockholm, Sweden.
    Silveira, A.
    Karolinska University Hospital, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska University Hospital, Stockholm, Sweden.
    Öhrvik, J.
    Karolinska University Hospital, Stockholm, Sweden.
    Bäcklund, A.
    Karolinska University Hospital, Stockholm, Sweden.
    Samnegård, A.
    Karolinska University Hospital, Stockholm, Sweden.
    Khademi, M.
    Karolinska University Hospital, Stockholm, Sweden.
    Hellenius, M.-L.
    Karolinska University Hospital, Stockholm, Sweden.
    Leander, K.
    Karolinska Institute, Stockholm, Sweden.
    Olsson, T.
    Karolinska University Hospital, Stockholm, Sweden.
    Uhlén, M.
    KTH-Royal Institute of Technology, Stockholm, Sweden.
    de Faire, U.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Eriksson, P.
    Karolinska University Hospital, Stockholm, Sweden.
    Hamsten, A.
    Karolinska University Hospital, Stockholm, Sweden.
    Plasma CD93 concentration is a potential novel biomarker for coronary artery disease2011In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 270, no 3, p. 229-236Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    A common nonsynonymous single nucleotide polymorphism (SNP) in the CD93 gene (rs3746731, Pro541Ser) has been associated with risk of coronary artery disease (CAD). CD93 is a transmembrane glycoprotein, which is detectable in soluble form in human plasma. We investigated whether the concentration of soluble CD93 in plasma is related to risk of myocardial infarction (MI) and CAD, using a case-control study of premature MI (n = 764) and a nested case-control analysis of a longitudinal cohort study of 60-year-old subjects (analysis comprising 844 of 4232 subjects enrolled at baseline). In addition, SNPs in the CD93 gene were studied in relation to plasma CD93 concentration and CD93 mRNA expression.

    METHODS AND RESULTS:

    A sensitive and specific enzyme-linked immunosorbent assay was established for determination of the plasma CD93 concentration. Subjects were divided into three groups according to tertiles of the distribution of CD93 concentration. Lower odds ratios for risk of MI and incidence of CAD were observed in the middle CD93 tertile (142-173 μg L(-1) ): odds ratio (95% confidence interval), 0.69 (0.49-0.97) and 0.61 (0.40-0.94), respectively. These associations were independent of traditional CAD risk factors. The minor allele of a SNP in the 3' untranslated region of CD93 (rs2749812) was associated with increased plasma CD93 concentrations (P = 0.03) and increased CD93 mRNA expression levels (P = 0.02).

    CONCLUSION:

    The results of the present study suggest that the concentration of soluble CD93 in plasma is a potential novel biomarker for CAD, including MI.

     

  • 20.
    Mälarstig, Anders
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Wågsäter, Dick
    Karolinska Institute, Stockholm, Sweden .
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden .
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden .
    Zar, Niklas
    Ryhov County Hospital, Jönköping, Sweden .
    Dimberg, Jan
    University College of Health Sciences, Jönköping, Sweden.
    Tumour-derived adhesion factor in colorectal cancer2009In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 2, no 6, p. 971-976Article in journal (Refereed)
    Abstract [en]

    Tumour-derived adhesion factor (TAF) has been shown to be associated with breast, prostate and colorectal cancer (CRC), acting as tumour suppressor or tumour promoter by mechanisms not as yet understood. Here, we comparatively analyzed the expression profile of TAF in plasma, tumour and paired normal tissue from patients with CRC. In addition, we investigated the relationship between TAF and systemic inflammation, mirrored by the elevation of interleukin-6 (IL-6) and TAF levels in plasma. Levels of TAF and IL-6 were determined by ELISA. Immunohistochemistry was performed to investigate the site of TAF expression. We also used a TaqMan system to investigate a TAF single nucleotide polymorphism (rs2041437) with a potential effect on CRC. TAF protein levels were significantly (Pless than0.001) higher in colorectal tumours than in normal tissue, and were increased in patients with Dukes stages B and C compared to A. Immunohistochemistry revealed heterogeneous TAF expression mainly in the epithelial cells of the cancer and normal tissue. The plasma TAF level was reduced in CRC patients compared with the controls (P=0.002), independent of the inflammatory marker IL-6. Regarding genotype and allelic distributions, significant differences between CRC patients and control subjects or associations between clinical characteristics and TAF levels in tissue and plasma were not observed. In conclusion, altered TAF protein expression in cancer tissue may be a potential biomarker in colorectal carcinogenesis. Further research exploring the regulation of TAF is required to evaluate whether TAF is linked to clinical outcome.

  • 21.
    Olofsson, P. S.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Jatta, K.
    University of Örebro, Sweden.
    Wågsäter, Dick
    University of Örebro, Sweden.
    Gredmark, S.
    Karolinska Institutet, Stockholm, Sweden.
    Hedin, U.
    Karolinska Institutet, Stockholm, Sweden.
    Paulsson-Berne, G.
    Karolinska Institutet, Stockholm, Sweden.
    Söderberg-Nauclér, C.
    Karolinska Institutet, Stockholm, Sweden.
    Hansson, G. K.
    Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, A.
    University of Örebro, Sweden.
    The antiviral cytomegalovirus inducible gene 5/viperin is expressed in atherosclerosis and regulated by proinflammatory agents2005In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 25, no 7, p. E113-E116Article in journal (Refereed)
    Abstract [en]

    Objective-Inflammatory processes play an important role in atherosclerosis, and increasing evidence implies that microbial pathogens and proinflammatory cytokines are involved in the development and activation of atherosclerotic lesions. To find new inflammatory genes, we explored the vascular transcriptional response to an activator of innate immunity bacterial lipopolysaccharides (LPSs). Methods and Results-Gene arrays identified the cytomegalovirus-inducible gene 5 (cig5)/viperin among the genes most potently induced by LPS in human vascular biopsies. Viperin was expressed by endothelial cells in atherosclerotic arteries and significantly elevated in atherosclerotic compared with normal arteries. In culture, cytomegalovirus infection, interferon-gamma, and LPS induced viperin expression. Conclusion-Viperin is expressed in atherosclerosis and induced in vascular cells by inflammatory stimuli and cytomegalovirus infection. The putative functions of viperin in atherosclerosis may relate to disease-associated microbes.

  • 22.
    Olofsson, Peder S.
    et al.
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Söderström, Leif Å.
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    University of Örebro, Sweden .
    Sheikine, Yuri
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden .
    Ocaya, Pauline
    University of Örebro, Sweden .
    Lang, Francois
    INSERM U601, Nantes, France.
    Rabu, Catherine
    INSERM U601, Nantes, France.
    Chen, Lieping
    Johns Hopkins University School of Medicine, Baltimore, USA.
    Rudling, Mats
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Aukrust, Pål
    University of Oslo, Norway .
    Hedin, Ulf
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Paulsson-Berne, Gabrielle
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Sirsjö, Allan
    University of Örebro, Sweden .
    Hansson, Göran K.
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice2008In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 117, no 10, p. 1292-1301Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Atherosclerosis is a multifactorial disease in which inflammatory processes play an important role. Inflammation underlies lesion evolution at all stages, from establishment to plaque rupture and thrombosis. Costimulatory molecules of the tumor necrosis factor superfamily such as CD40/CD40L and OX40/OX40L have been implicated in atherosclerosis.

    METHODS AND RESULTS:

    This study shows that the tumor necrosis factor superfamily members CD137 and CD137 ligand (CD137L), which play a major role in several autoimmune diseases, may constitute a pathogenic pair in atherogenesis. We detected CD137 protein in human atherosclerotic lesions not only on T cells but also on endothelial cells and showed that CD137 in cultured endothelial cells and smooth muscle cells was induced by proinflammatory cytokines implicated in atherosclerosis. Activation of CD137 by CD137L induced adhesion molecule expression on endothelial cells and reduced smooth muscle cell proliferation. In addition, treatment of atherosclerosis-prone apolipoprotein E-deficient mice with a CD137 agonist caused increased inflammation. T-cell infiltration, mainly of CD8(+) cells, and expression of the murine major histocompatibility complex class II molecule I-A(b) increased significantly in atherosclerotic lesions, as did the aortic expression of proinflammatory cytokines.

    CONCLUSIONS:

    Taken together, these observations suggest that CD137-CD137L interactions in the vasculature may contribute to the progression of atherosclerosis via augmented leukocyte recruitment, increased inflammation, and development of a more disease-prone phenotype.

  • 23.
    Ovchinnikova, Olga
    et al.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Robertson, Anna-Karin L.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Folco, Eduardo J.
    Harvard Medical School, Boston, Massachusetts, USA.
    Hyry, Marjo
    University of Oulu, Finland.
    Myllyharju, Johanna
    University of Oulu, Finland .
    Eriksson, Per
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Libby, Peter
    Harvard Medical School, Boston, Massachusetts, USA.
    Hansson, Göran K.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    T-Cell Activation Leads to Reduced Collagen Maturation in Atherosclerotic Plaques of Apoe−/− Mice2009In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 174, no 2, p. 693-700Article in journal (Refereed)
    Abstract [en]

    Rupture of the collagenous, fibrous cap of an atherosclerotic plaque commonly causes thrombosis. Activated immune cells can secrete mediators that jeopardize the integrity of the fibrous cap. This study aimed to determine the relationship between T-cell-mediated inflammation and collagen turnover in a mouse model of experimental atherosclerosis. Both Apoe(-/-) x CD4dnT beta RII mice with defective transforming growth factor-beta receptors in T cells (and hence released from tonic suppression of T-cell activation) and lesion size-matched Apoe(-/-) mice were used. Picrosirius red staining showed a lower content of thick mature collagen fibers in lesions of Apoe(-/-) x CD4dnT beta RII mice, although both groups had similar levels of procollagen type I or M mRNA and total collagen content in lesions. Analysis of both gene expression and protein content showed a significant decrease of lysyl oxidase, the extracellular enzyme needed for collagen cross-linking, in aortas of Apoe(-/-) - CD4dnT beta RII mice. T-cell-driven inflammation provoked a selective and limited increase in the expression of proteinases that catabolize the extracellular matrix. Atheromata of Apoe(-/-) - CD4dnT beta RII mice had increased levels of matrix metalloproteinase-13 and cathepsin S mRNAs and of the active form of cathepsin S protein but no increase was detected in collagen fragmentation. our results suggest that exaggerated T-cell-driven inflammation limits collagen maturation in the atherosclerotic plaque while having little effect on collagen degradation.

  • 24.
    Paloschi, Valentina
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Kurtovic, Sanela
    Karolinska Institutet, Stockholm, Sweden.
    Folkersen, Lasse
    Karolinska Institutet, Stockholm, Sweden.
    Gomez, Delphine
    University of Paris 07, France .
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden.
    Roy, Joy
    Karolinska Institutet, Stockholm, Sweden.
    Petrini, Johan
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Maria J.
    Karolinska Institutet, Stockholm, Sweden.
    Caidahl, Kenneth
    Karolinska Institutet, Stockholm, Sweden.
    Hamsten, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Liska, Jan
    Karolinska Institutet, Stockholm, Sweden.
    Michel, Jean-Baptiste
    University of Paris 07, France .
    Franco-Cereceda, Anders
    Karolinska Institutet, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institutet, Stockholm, Sweden.
    Impaired Splicing of Fibronectin Is Associated With Thoracic Aortic Aneurysm Formation in Patients With Bicuspid Aortic Valve2011In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 31, no 3, p. 691-697Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Thoracic aortic aneurysm is a common complication in patients with bicuspid aortic valve (BAV). Alternatively spliced extra domain A (EDA) of fibronectin (FN) has an essential role in tissue repair. Here we analyze the expression of FN spliceforms in dilated and nondilated ascending aorta of tricuspid aortic valve (TAV) and BAV patients.

    METHODS AND RESULTS:

    The mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=40) and BAV (n=69). EDA and extra domain B (EDB) expression was increased in dilated aorta from TAV patients compared with nondilated aorta (P<0.001 and P<0.05, respectively). In contrast, EDA expression was not increased in dilated aorta from BAV patients (P=0.25), whereas EDB expression was upregulated (P<0.01). The expression of EDA correlated with maximum aortic diameter in TAV (ρ=0.58) but not in BAV (ρ=0.15) patients. Protein analyses of EDA-FN showed concordant results. Transforming growth factor-β treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in cultured medial cells from TAV patients but not in cells derived from BAV patients. Gene set enrichment analysis together with multivariate and univariate data analyses of mRNA expression suggested that differences in the transforming growth factor-β signaling pathway may explain the impaired EDA inclusion in BAV patients.

    CONCLUSIONS:

    Decreased EDA expression may contribute to increased aneurysm susceptibility of BAV patients.

  • 25.
    Popov, Sergej
    et al.
    Karolinska University Hospital, Solna, Stockholm, Sweden.
    Silveira, Angela
    Karolinska University Hospital, Solna, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska University Hospital, Solna, Stockholm, Sweden.
    Takemori, Hiroshi
    National Institute for Biomedical Innovation, Osaka, Japan .
    Oguro, Ryousuke
    Osaka University, Japan .
    Matsumoto, Sachiko
    National Cerebral and Cardiovascular Center, Suita, Japan .
    Sugimoto, Ken
    Osaka University, Japan .
    Kamide, Kei
    Osaka University, Japan .
    Hirose, Takuo
    Tohoku University, Sendai, Japan.
    Satoh, Michihiro
    Tohoku University, Sendai, Japan.
    Metoki, Hirohito
    Tohoku University, Sendai, Japan.
    Kikuya, Masahiro
    Tohoku University, Sendai, Japan.
    Ohkubo, Takayoshi
    Tohoku University, Sendai, Japan .
    Katsuya, Tomohiro
    Osaka University, Japan .
    Rakugi, Hiromi
    Osaka University, Japan .
    Imai, Yutaka
    Tohoku University, Sendai, Japan.
    Sanchez, Fabio
    Karolinska University Hospital, Solna, Stockholm, Sweden .
    Leosdottir, Margret
    Lund University, Sweden .
    Syvänen, Ann-Christine
    Uppsala University, Sweden .
    Hamsten, Anders
    Karolinska University Hospital, Solna, Stockholm, Sweden .
    Melander, Olle
    Lund University, Sweden .
    Bertorello, Alejandro M.
    Karolinska University Hospital, Solna, Stockholm, Sweden .
    Salt-inducible kinase 1 influences Na+,K+-ATPase activity in vascular smooth muscle cells and associates with variations in blood pressure2011In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 29, no 12, p. 2395-2403Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Essential hypertension is a complex condition whose cause involves the interaction of multiple genetic and environmental factors such as salt intake. Salt-inducible kinase 1 (SIK1) is a sucrose-nonfermenting-like kinase isoform that belongs to the AMPK (5' adenosine monophosphate-activated protein kinase) family. SIK1 activity is increased by high salt intake and plays an essential role in regulating the plasma membrane Na(+),K(+)-ATPase. The objective of this study was to examine whether SIK1 is present in vascular smooth muscle cells (VSMCs) and endothelial cells, whether it affects VSMC Na(+),K(+)-ATPase activity and whether human SIK1 (hSIK1) represents a potential candidate for blood pressure regulation.

    METHODS:

    Localization of SIK1 was performed using immunohistochemistry, mRNA and western blot. Functional assays (Na(+),K(+)-ATPase activity) were performed in VSMCs derived from rat aorta. Genotype-phenotype association studies were performed in three Swedish and one Japanese population-based cohorts.

    RESULTS:

    SIK1 was localized in human VSMCs and endothelial cells, as well as a cell line derived from rat aorta. A nonsynonymous single nucleotide polymorphism in the hSIK1 gene exon 3 (C→T, rs3746951) results in the amino acid change (15)Gly→Ser in the SIK1 protein. SIK1-(15)Ser was found to increase plasma membrane Na(+),K(+)-ATPase activity in cultured VSMC line from rat aorta. Genotype-phenotype association studies in three Swedish and one Japanese population-based cohorts suggested that T allele (coding for (15)Ser) was associated with lower blood pressure (P = 0.005 for SBP and P = 0.002 for DBP) and with a decrease in left ventricular mass (P = 0.048).

    CONCLUSION:

    The hSIK1 appears to be of potential relevance within VSMC function and blood pressure regulation.

  • 26.
    Rullman, E
    et al.
    Karolinska Institute, Sweden .
    Olsson, K
    Karolinska Institute, Sweden .
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Gustafsson, T
    Karolinska Institute, Sweden .
    Circulating MMP-9 during exercise in humans2013In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 113, no 5, p. 1249-1255Article in journal (Refereed)
    Abstract [en]

    Matrix metalloproteinase 9 (MMP-9) is a member of a family of zinc-dependent endopeptidases capable of degrading extracellular matrix (ECM) proteins. A single bout of exercise increases levels of activated MMP-9 in skeletal muscle and in the circulation. However, whether the exercise-induced activation of MMP-9 is associated with ECM remodeling and the cellular source behind MMP-9 in the circulation is not known. In the present study ten healthy male subjects performed a single cycle exercise bout and arterial and venous femoral blood was collected. To test if exercise induces basal lamina degradation and if circulating levels of MMP-9 is related to a release from the exercising muscle, arteriovenous differences of collagen IV and MMP-9 were measured by ELISA and zymography, respectively. Furthermore, markers of neutrophil degranulation elastase and neutrophil gelatinase-associated lipocalin (NGAL) were measured by ELISA. Plasma levels of collagen IV increased during the exercise bout and an increased arteriovenous difference of collagen IV was noted at 27 min of exercise. Plasma levels of MMP-9 were increased at both 27 and 57 min of exercise but no arteriovenous difference was noted. No changes over time were detected for elastase and NGAL. The observed release of collagen IV from the exercising muscle indicate basal lamina turnover following a single bout of exercise. No detectable release of MMP-9 was observed, suggesting that the increase in plasma MMP-9 could come from a source other than the skeletal muscle.

  • 27.
    Rullman, E.
    et al.
    Karolinska Institutet, Stockholm, Sweden .
    Rundqvist, H.
    Karolinska Institutet, Stockholm, Sweden .
    Wågsäter, Dick
    Karolinska Institutet, Stockholm, Sweden .
    Fischer, H.
    Karolinska Institutet, Stockholm, Sweden .
    Eriksson, P.
    Karolinska Institutet, Stockholm, Sweden .
    Sundberg, C. J.
    Karolinska Institutet, Stockholm, Sweden .
    Jansson, E.
    Karolinska Institute, Stockholm, Sweden.
    Gustafsson, T.
    Karolinska Institutet, Stockholm, Sweden .
    A single bout of exercise activates matrix metalloproteinase in human skeletal muscle2007In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 102, no 6, p. 2346-2351Article in journal (Refereed)
    Abstract [en]

    The aims of this study were 1) to characterize changes in matrix metalloproteinase (NIMP), endostatin, and vascular endothelial growth factor (VEGF)-A expression in skeletal muscle in response to a single bout of exercise in humans; and 2) to determine if any exchange of endostatin and VEGF-A between circulation and the exercising leg is associated with a change in the tissue expression or plasma concentration of these factors. Ten healthy males performed 65 min of cycle exercise, and muscle biopsies were obtained from the vastus lateralis muscle at rest and immediately and 120 min after exercise. In the muscle biopsies, measurements of mRNA expression levels of MMP-2, MMP-9, MMP-14, and tissue inhibitor of metalloproteinase; VEGF and endostatin protein levels; and NIMP activities were performed. Femoral arterial and venous concentrations of VEGF-A and endostatin were determined before, during, and 120 min after exercise. A single bout of exercise increased MMP-9 mRNA and activated MMP-9 protein in skeletal muscle. No measurable increase of endostatin was observed in the skeletal muscle or in plasma following exercise. A concurrent increase in skeletal muscle VEGF-A mRNA and protein levels was induced by exercise, with no signs of peripheral uptake from the circulation. However, a decrease in plasma VEGF-A concentration occurred following exercise. Thus 1) a single bout of exercise activated the MMP system without any resulting change in tissue endostatin protein levels, and 2) the increased VEGF-A protein levels are due to changes in the skeletal muscle tissue itself. Other mechanisms are responsible for the observed exercise-induced decrease in VEGF-A in plasma.

  • 28.
    Rullman, Eric
    et al.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Norrbom, Jessica
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Strömberg, Anna
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Wågsäter, Dick
    Karolinska Institute, Stockholm, Sweden.
    Rundqvist, Helene
    Karolinska Institute, Stockholm, Sweden.
    Haas, Tara
    York University,Toronto, Ontario, Canada .
    Gustafsson, Thomas
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Endurance exercise activates matrix metalloproteinases in human skeletal muscle2009In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 106, no 3, p. 804-812Article in journal (Refereed)
    Abstract [en]

    In the present study, the effect of exercise training on the expression and activity of matrix metalloproteinases (MMPs) in the human skeletal muscle was investigated. Ten subjects exercised one leg for 45 min with restricted blood flow and then exercised the other leg at the same absolute workload with unrestricted blood flow. The exercises were conducted four times per week for 5 wk. Biopsies were taken from the vastus lateralis muscles of both legs at rest before the training period, after 10 days and 5 wk of training, and 2 h after the first exercise bout for analysis of MMP and tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA, enzyme activity, and protein expression. Levels of MMP-2, MMP-14, and TIMP-1 mRNA in muscle tissue increased after 10 days of training regardless of blood flow condition. MMP-2 mRNA level in laser-dissected myofibers and MMP-2 activity in whole muscle increased with training. The level of MMP-9 mRNA and activity increased after the first bout of exercise. Although MMP-9 mRNA levels appeared to be very low, the activity of MMP-9 after a single bout of exercise was similar to that of MMP-2 after 10 days of exercise. MMP-2 and MMP-9 protein was both present throughout the extracellular matrix of the muscle, both around fibers and capillaries, but MMP-2 was also present within the skeletal muscle fibers. These results show that MMPs are activated in skeletal muscle in nonpathological conditions such as voluntary exercise. The expression and time pattern indicate differences between the MMPs in regards of production sites as well as in the regulating mechanism

  • 29.
    Sevastianova, Ksenia
    et al.
    Minerva Institute for Medical Research, Helsinki, Finland.
    Sutinen, Jussi
    Helsinki University Central Hospital, Finland .
    Greco, Dario
    University of Helsinki, Finland .
    Sievers, Meline
    Medizinische Universitätsklinik, Freiburg, Germany .
    Salmenkivi, Kaisa
    University of Helsinki, Finland .
    Perttila, Julia
    Minerva Institute for Medical Research, Helsinki, Finland.
    Olkkonen, Vesa M.
    Minerva Institute for Medical Research, Helsinki, Finland.
    Wågsäter, Dick
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden .
    Lidell, Martin E.
    University of Gothenburg, Sweden .
    Enerback, Sven
    University of Gothenburg, Sweden .
    Eriksson, Per
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Walker, Ulrich A.
    University of Basel, Switzerland .
    Auvinen, Petri
    University of Helsinki, Finland .
    Ristola, Matti
    Helsinki University Central Hospital, Finland .
    Yki-Järvinen, Hannele
    Helsinki University Central Hospital, Finland .
    Comparison of Dorsocervical With Abdominal Subcutaneous Adipose Tissue in Patients With and Without Antiretroviral Therapy-Associated Lipodystrophy2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 7, p. 1894-1900Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Combination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intra-abdominally. No fat is lost dorsocervically and it can even accumulate in this region (buffalo hump). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1-infected cART-treated patients with (cART+LD+) and without (cART+LD-) lipodystrophy.

    RESEARCH DESIGN AND METHODS:

    We used histology, microarray, PCR, and magnetic resonance imaging to compare dorsocervical and abdominal subcutaneous adipose tissue in cART+LD+ (n=21) and cART+LD- (n=11).

    RESULTS:

    Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA; copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD-. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical versus abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot.

    CONCLUSIONS:

    Because mtDNA is depleted even in the nonatrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal subcutaneous adipose tissue is in expression of homeobox genes.

  • 30.
    Sievers, M.
    et al.
    Medizinische Universitätsklinik, Freiburg, Germany.
    Walker, U. A.
    Medizinische Universitätsklinik, Freiburg, Germany; .
    Sevastianova, K.
    Helsinki University Central Hospital, Finland.
    Setzer, B.
    Medizinische Universitätsklinik, Freiburg, Germany.
    Wågsäter, Dick
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden .
    Eriksson, P.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden .
    Yki-Järvinen, H.
    Helsinki University Central Hospital, Finland.
    Sutinen, J.
    Helsinki University Central Hospital, Finland.
    Gene Expression and Immunohistochemistry in Adipose Tissue of HIV Type 1-Infected Patients with Nucleoside Analogue Reverse-Transcriptase Inhibitor-Associated Lipoatrophy2009In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 200, no 2, p. 252-262Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Long-term use of both zidovudine (AZT) and stavudine (d4T) is associated with lipoatrophy, but it occurs possibly through different mechanisms.

    METHODS:

    Surgical biopsy specimens of subcutaneous adipose tissue were obtained from 18 human immunodeficiency virus type 1 (HIV-1)-infected lipoatrophic patients (the LA+ group) who were treated with either zidovudine (the AZT+LA+ group; n = 10) or stavudine (the d4T+LA+ group; n = 8) and from 10 nonlipoatrophic HIV-1-infected patients (the LA- group) who received antiretroviral therapy. Mitochondrial DNA (mtDNA) copy numbers, gene expression, and immunohistochemistry data were analyzed.

    RESULTS:

    mtDNA copy numbers were significantly reduced in the LA+ group, compared with the LA- group, and in the d4T+LA+ group, compared with the AZT+LA+ group. The ratio of mtDNA-encoded cytochrome COX3 to nuclear DNA-encoded COX4 expression was significantly lower in the LA+ group than in the LA- group. Compared with the LA- group, the LA+ group had significantly lower expression of genes involved in adipogenesis (SREBP1c and CEBPB), lipid (fatty acid synthase), and glucose (GLUT4) metabolism. Expression of genes involved in mitochondrial biogenesis (PGC1B), apoptosis (FAS), inflammation (IL1B), oxidative stress (PCNA and SOD1), and lamin B was significantly higher in the LA+ group than in the LA- group. The d4T+LA+ group had significantly lower expression of genes involved in mitochondrial biogenesis (POLG1), energy metabolism (the COX3/COX4 ratio), adipogenesis (SREBP1c and CEBPA), perilipin, and hexokinase than did the AZT+LA+ group. There were 7-fold more macrophages in adipose tissue specimens obtained from patients in the LA+ group, compared with the LA- group.

    CONCLUSIONS:

    Lipoatrophy is characterized by mtDNA depletion, inflammation, and signs of apoptosis. Changes were more profound in the d4T+LA+ group than in the AZT+LA+ group

  • 31.
    Sirsjö, Allan
    et al.
    Karolinska Institute, Sweden; University of Örebro, Sweden.
    Löfving, Anders
    Karolinska Institute, Sweden.
    Hansson, Göran K.
    Karolinska Institute, Sweden.
    Wågsäter, Dick
    Karolinska Institute, Sweden; University of Örebro, Sweden.
    Tokuno, S.
    Karolinska Institute, Sweden.
    Valen, G.
    Karolinska Institute, Sweden.
    Deficiency of nitric oxide synthase 2 results in increased neointima formation in a mouse model of vascular injury2003In: Journal of Cardiovascular Pharmacology, ISSN 0160-2446, E-ISSN 1533-4023, Vol. 41, no 6, p. 897-902Article in journal (Refereed)
    Abstract [en]

    Restenosis frequently occurs after arterial interventions. The inducible form of nitric oxide synthase (NOS2) may both promote and inhibit neointima formation. This study investigated the role of NOS2 for neointima formation in a mouse model of carotid artery injury. The common carotid artery was ligated in anesthetized mice. Homozygous NOS2 knockout mice were compared with wild-type B6/129 mice or wild-type mice treated with the pharmacologic NOS2 inhibitor aminoguanidine given orally daily after ligation (n = 6-8 in each group). Vessels were harvested for quantification of lesion size 4 weeks later, or serially after ligation for tissue analysis. mRNA for NOS2 increased 1-4 days after ligation of the carotid artery. Cell proliferation could be visualized with an antibody against proliferating cell nuclear antigen. An intimal smooth muscle cell layer, confirmed by an alpha-actin antibody, was observed in the lumen 4 weeks after injury. Inhibition of NOS2 by either pharmacologic or genetic approaches tended to increase the area of intima formation (P = 0.13 or P less than 0.05, respectively) and increased the intima/media ratio (P = 0.14 and P less than 0.01, respectively). Inhibition of NOS2 by two different approaches increased neointima formation in a mouse model of mechanical vessel injury, indicating that the NOS2 expressed in the injured vessel wall is beneficial.

  • 32.
    Slind Olsen, Renate
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Laboratory Services, Ryhov County Hospital, Jönköping, Sweden.
    Andersson, Roland E
    Department of Surgery, Ryhov County Hospital, Jönköping Sweden.
    Zar, Niklas
    Department of Surgery, Ryhov County Hospital, Jönköping Sweden.
    Löfgren, Sture
    Department of Clinical Microbiology, Ryohov County Hospital, Jönköping .
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Matussek, Andreas
    Laboratory Services, Ryhov County Hospital, Jönköping, Sweden.
    Dimberg, Jan
    Natural Science and Biomedicine, University College of Health Sciences, Jönköping, Sweden.
    Prognostic significance of PLA2G4C gene polymorphism in patients with stage II colorectal cancer.2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 4, p. 474-479Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Phospholipase A2 Group IV C (PLA2G4C) catalyzes the release of certain fatty acids from phospholipids and plays a role in a range of physiological functions, such as remodeling of cell membranes and the production of prostaglandins. Furthermore, it has been proposed that PLA2G4C plays an important role in breast cancer cell chemotaxis. This study aimed to investigate the effect of a single nucleotide polymorphism (SNP) rs1549637 (T>A) of the PLA2G4C gene on the prognosis of colorectal cancer (CRC).

    MATERIAL AND METHODS: Whole blood DNA was extracted from 381 patients with CRC and 618 controls, and a TaqMan SNP genotyping assay was used to determine the distribution of the genotypes. Cancer-specific and disease-free survival was analyzed by Kaplan-Meier graphs and by uni- and multivariable Cox regression.

    RESULTS: The cancer-specific survival differed between the genotypes (p = 0.019) and the carriers of the A allele were associated with the highest risk of CRC death, with a hazard ratio (HR) of 1.72 [95% confidence interval (CI) 1.17-2.53, p = 0.006] compared with homozygous carriers of the T allele. This increased mortality in the carriers with the allele A was especially marked in stage II with an HR of 3.84 (95% CI 1.51-9.78, p = 0.005).

    CONCLUSION: The A allele in PLA2G4C SNP (rs1549637) is associated with a worse prognosis in patients with CRC, especially in stage II disease, and it could be a potential prognostic biomarker in the planning of individual adjuvant therapy in stage II patients.

  • 33.
    Slind Olsen, Renate
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. County Hospital Ryhov, Sweden.
    Lindh, Mikael
    County Hospital Ryhov, Sweden.
    Vorkapic, Emina
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Andersson, Roland E.
    County Hospital Ryhov, Sweden.
    Zar, Niklas
    County Hospital Ryhov, Sweden.
    Lofgren, Sture
    County Hospital Ryhov, Sweden.
    Dimberg, Jan
    School Health Science, Sweden.
    Matussek, Andreas
    County Hospital Ryhov, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    CD93 gene polymorphism is associated with disseminated colorectal cancer2015In: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 30, no 7, p. 883-890Article in journal (Refereed)
    Abstract [en]

    Cluster of differentiation 93 (CD93) is involved in apoptosis and inflammation and has a suggested role in angiogenesis, and all of which are involved in the development and dissemination of cancer. We evaluated the expression of CD93 and the association with two single nucleotide polymorphisms (SNPs), rs2749812 and rs2749817, as possible biomarkers in colorectal cancer (CRC). Tissue levels and plasma levels of CD93 were measured using an enzyme-linked immunosorbent assay (ELISA). Expression of CD93 was determined by immunohistochemistry, western blot and gene expression analysis. Genotype frequencies were established for the SNPs by real-time polymerase chain reaction (PCR), and the association with tumour stage and survival was analysed. Total CD93 levels were 82 % higher (P less than 0.001) in tumours compared to matched normal tissues. Mean levels of soluble CD93 in plasma were 30 % lower (P less than 0.001) in the patients compared to the controls. The T/T genotype of SNP rs2749817 was more common in stage IV patients, with consequently higher risk of CRC death (T/T vs. C/C and C/T; hazard ratio (HR) = 1.73, 95 % confidence interval (CI) = 1.11-2.67, P = 0.014), and was associated with a higher risk of CRC recurrence after radical operation (T/T vs. C/C and C/T; HR = 2.07, CI = 1.22-3.51, P = 0.007). We showed that the T/T genotype of SNP rs2749817 is associated with disseminated cancer at diagnosis and an increased recurrence rate after radical operation. Patients with this genotype may benefit from early identification.

  • 34.
    Uggla, Bertil
    et al.
    Örebro University Hospital, Sweden .
    Ståhl, Elisabeth
    Örebro University Hospital, Sweden.
    Wågsäter, Dick
    Örebro University, Sweden.
    Paul, Christer
    Huddinge University Hospital, Stockholm, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital, Sweden.
    Sirsjö, Allan
    Örebro University, Sweden.
    Tidefelt, Ulf
    Örebro University Hospital, Sweden .
    BCRP mRNA expression v. clinical outcome in 40 adult AML patients2005In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, no 2, p. 141-146Article in journal (Refereed)
    Abstract [en]

    Efflux pumps are considered being mechanisms behind drug resistance in acute myeloid leukaemia (AML). A recently described efflux pump, breast cancer resistance protein (BCRP), can be expressed in AML, but its clinical importance is uncertain, In this study BCRP mRNA expression was determined in samples from 40 AML patients by real-time RT-PCR. The expression varied from negative to 76 times that of control cells. There was no difference in BCRP mRNA expression between patients responding to induction treatment and non-responders. However, in the group of responders, the 14 patients with the highest expression had significantly shorter overall Survival (mean 38 months, SEM 15 months) than the 14 patients with the lowest (74 months, SEM 16 months) (P = 0.047). This suggests a possible role of BCRP in drug resistance in AML.

  • 35.
    Viet, Hung Trinh
    et al.
    Vietnam National University, Hanoi, Vietnam .
    Wågsäter, Dick
    University of Örebro, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Dimberg, Jan
    University College of Health Sciences, Jönköping, Sweden.
    Interleukin-1 receptor antagonist gene polymorphism in human colorectal cancer2005In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 14, no 4, p. 915-918Article in journal (Refereed)
    Abstract [en]

    Several studies indicate that local immunoregulation and associated cytokines have a putative role in the development of cancer. There is evidence that pro-inflammatory cytokines such as interleukin-1 (IL-1) are critically involved with tumour progression. IL-1 receptor antagonist (IL-1Ra) is known to down regulate and limit the inflammatory response. Therefore we attempted to examine the influence of the known polymorphism of the IL-1Ra gene on the development of human colorectal cancer (CRC). The study included 125 patients with CRC and 134 controls. Variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-Ra gene was analysed by the polymerase chain reaction method. There was a significant difference in genotype distribution between CRC patients and controls (P=0.025) and also in allelic frequencies (P=0.012). In detail the carriage rate of allele 3 in CRC patients was significantly increased compared with controls (P=0.007). We also found that the allelic distribution differs significantly between colon and rectum (P=0.041) and that allele 3 was overabundant in colon. The frequency of allele I in CRC patients with localized disease (Dukes A+B) was higher compared with disseminated disease (Dukes C+D), (P=0.035). These findings therefore suggest that the IL-1Ra polymorphism is associated with colorectal carcinogenesis.

  • 36.
    Villard, Christina
    et al.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden .
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Karolinska Institute, Stockholm, Sweden.
    Swedenborg, Jesper
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden .
    Eriksson, Per
    Karolinska Institute, Stockholm, Sweden.
    Hultgren, Rebecka
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden .
    Biomarkers for Abdominal Aortic Aneurysms From a Sex Perspective2012In: Gender Medicine, ISSN 1550-8579, E-ISSN 1878-7398, Vol. 9, no 4, p. 259-266Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Abdominal aortic aneurysms (AAAs) differ in men and women. Women are older at diagnosis, have a higher risk of rupture, and worse outcome after surgery compared with men. The higher occurrence of AAAs in men accounts for the dominance of men in biomarker analyses.

    OBJECTIVE:

    The primary aim of this study was to investigate levels of established biomarkers for AAA in men and women, and the secondary aim was to compare biomarker levels in women with and without AAAs.

    METHODS:

    In this prospective case-control study, blood samples were collected from 16 women and 18 men with AAAs ≥5.5 cm, from 20 women with AAAs <5.5 cm, and from 18 women with peripheral artery disease (PAD). Plasma concentrations of matrix metalloproteinase (MMP) -2, -9, and -13; tissue inhibitor of MMP-1 (TIMP-1); plasminogen activator inhibitor 1 (PAI-1); high-sensitivity C-reactive protein (hsCRP); and estradiol levels were analyzed by ELISA. An ultrasound examination was performed in women with PAD to exclude an AAA.

    RESULTS:

    Age and other comorbid conditions were similar between men and women with AAAs. Women with AAAs had higher levels of MMP-9 compared with men with equally large AAAs (42.8 ng/mL vs 36.2 ng/mL, P = 0.036) and lower levels of estradiol (30.0 pmoL vs 86.5 pmol/L, P < 0.001). Women with AAAs had lower levels of MMP-9 compared with women without (59.5 ng/mL vs 132.6 ng/mL, P = 0.010). There was no significant difference in the plasma levels of MMP-2, MMP-13, hsCRP, PAI-1, TIMP-1, and estradiol between women with and without AAAs.

    CONCLUSION:

    The higher levels of MMP-9 in women compared with men with equally large AAAs could suggest that MMP-9 is a biomarker related to the sex differences in aneurysm development. The lower levels of estradiol in women with AAAs compared with men suggest that the possible protective effect of endogenous estrogen cannot be explained by a difference in circulating levels of estradiol.

  • 37.
    Vorkapic, Emina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Dugic, Elma
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Roy, Joy
    Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Mäyränpää, Mikko I.
    Department of Pathology, University of Helsinki, Helsinki, Finland / HUSLAB, Division of Pathology, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
    Eriksson, Per
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm2016In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 249, p. 101-109Article in journal (Refereed)
    Abstract [en]

    AbstractBackground Abdominal aortic aneurysm (AAA) is characterized by vascular remodeling with increased infiltration of inflammatory cells and apoptosis/modulation of vascular smooth muscle cells (SMCs). Imatinib is a selective inhibitor of several tyrosine kinases, including PDGF receptors, Abl, and c-kit. The objective of this study was to characterize the potential protective role of imatinib on AAA development and the molecular mechanisms involved. Methods Male ApoE−/− mice were infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Daily treatment with 10 mg/kg imatinib, or tap water as control, was provided via gavage for 4 weeks. Results Treatment with imatinib was found to decrease the aortic diameter and vessel wall thickness, mediated by multiple effects. Imatinib treatment in AngII infused mice resulted in a reduced cellular infiltration of CD3ε positive T lymphocytes by 86% and reduced gene expression of mast cell chymase by 50% compared with AngII infused mice lacking imatinib. Gene expression analysis of SMC marker SM22α demonstrated an increase by 48% together with a more intact medial layer after treatment with imatinib as evaluated with SM22α immunostaining. Conclusion Present findings highlight the importance of tyrosine kinase pathways in the development of AAA. Our results show, that imatinib treatment inhibits essential mast cell, T lymphocyte and SMC mediated processes in experimental AAA. Thus, our results support the idea that tyrosine kinase inhibitors may be useful in the treatment of pathological vascular inflammation and remodeling in conditions like AAA.

  • 38.
    Vorkapic, Emina
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Lundberg, Anna M.
    Karolinska University Hospital Solna, Sweden.
    Mayranpaa, Mikko I.
    University of Helsinki, Finland; University of Helsinki, Finland.
    Eriksson, Per
    Karolinska Institute, Sweden.
    Wågsäter, Dick
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    TRIF adaptor signaling is important in abdominal aortic aneurysm formation2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 241, no 2, p. 561-568Article in journal (Refereed)
    Abstract [en]

    Objective: Abdominal aortic aneurysm (AAA) is characterized by inflammation, loss of smooth muscle cells (SMCs), and degradation of the extracellular matrix in the vessel wall. Innate immune receptors such as Toll-like receptors (TLRs) were recently shown to regulate immunological processes leading to the formation and progression of atherosclerotic plaques as well as to other cardiovascular pathologies. Our aim was to investigate whether blockage of TLR signaling, under the control of TIR domain-containing adaptor protein including IFN-beta (TRIF), could inhibit the inflammatory response and AAA development in mice. Results: In human AAA, an increased TLR3 and TLR4 expression in association with macrophages and T lymphocytes was demonstrated with immunohistochemical analysis. Angiotensin (Ang) II-induced aneurysm formation was significantly reduced by 30% in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice. Morphologically, AngII-infused ApoE(-/-)Trif(-/-) mice had a more intact cellular and extracellular matrix while ApoE(-/-) mice infused with AngII displayed an increased medial thickness associated with aortic dissection, thrombus formation, and a more disorganized vessel wall. Gene expression analysis of the abdominal aorta revealed a profound decrease of the inflammatory genes CD68 (P less than 0.05), CD11b (P less than 0.05), and TNF-alpha (P less than 0.05) and the protease gene MMP-12 (P less than 0.01) in ApoE(-/-)Trif(-/-) mice compared to ApoE(-/-) mice infused with AngII. Conclusion: Our results suggest that signaling through TRIF is important for the inflammatory response of AngII-induced AAA and that blockage of the TRIF pathway reduces vascular inflammation and protects against AAA formation. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

  • 39.
    Wuttge, Dirk M.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Zhou, Xinghua
    Karolinska Institute, Stockholm, Sweden.
    Sheikine, Yuri
    Karolinska Institute, Stockholm, Sweden.
    Wågsäter, Dick
    University of Örebro, Sweden .
    Stemme, Veronika
    Karolinska Institute, Stockholm, Sweden.
    Hedin, Ulf
    Karolinska Institute, Stockholm, Sweden.
    Stemme, Sten
    Karolinska Institute, Stockholm, Sweden.
    Hansson, Göran K.
    Karolinska Institute, Stockholm, Sweden.
    Sirsjö, Allan
    University of Örebro, Sweden.
    CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions2004In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 24, no 4, p. 750-755Article in journal (Refereed)
    Abstract [en]

    Objective-Atherosclerosis is an inflammatory disease. Several chemokines are important for monocyte/macrophage and T-cell recruitment to the lesion. CXCL16 is a recently discovered chemokine that is expressed in soluble and transmembrane forms, ligates CXCR6 chemokine receptor, and guides migration of activated Th1 and Tc1 cells. It is identical to scavenger receptor SR-PSOX, which mediates uptake of oxidized low-density lipoprotein. We investigated whether CXCL16 expression is controlled by interferon-gamma (IFN-gamma)-cytokine abundant in atherosclerotic lesions. Methods and Results-CXCL16 and CXCR6 expression was identified by polymerase chain reaction and histochemistry in atherosclerotic lesions from humans and apolipoprotein-E-deficient mice. In vitro IFN-gamma induced CXCL16 in human monocytic THP-1 cells and primary human monocytes, which led to increased uptake of oxidized low-density lipoprotein in THP-1 cells, which could be blocked by peptide antibodies against CXCL16. In vivo IFN-gamma induced CXCL16 expression in murine atherosclerotic lesions. Conclusions-We demonstrate a novel role of IFN-gamma in foam cell formation through upregulation of CXCL16/SR-PSOX. CXCR6 expression in the plaque confirms the presence of cells able to respond to CXCL16. Therefore, this chemokine/scavenger receptor could serve as a molecular link between lipid metabolism and immune activity in the atherosclerotic lesion.

  • 40.
    Wågsäter, Dick
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Björk, Hanna
    Karolinska Institute, Stockholm, Sweden.
    Zhu, Chaoyong
    Karolinska Institute, Stockholm, Sweden.
    Björkegren, Johan
    Karolinska Institute, Stockholm, Sweden.
    Valen, Guro
    University of Oslo, Norway .
    Hamsten, Anders
    Karolinska Institute, Stockholm, Sweden.
    Eriksson, Per
    Karolinska Institute, Stockholm, Sweden.
    ADAMTS-4 and-8 are inflammatory regulated enzymes expressed in macrophage-rich areas of human atherosclerotic plaques2008In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 196, no 2, p. 514-522Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Remodeling of extracellular matrix (ECM) plays an important role in inflammatory disorders such as atherosclerosis. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently described family of proteinases that is able to degrade the ECM proteins aggrecan and versican expressed in blood vessels. The purpose of the present study was to analyze the expression and regulation of several ADAMTSs before and after macrophage differentiation and after stimulation with IFN-gamma, IL-1beta and TNF-alpha. ADAMTS expression was also examined during atherosclerosis development in mice and in human atherosclerotic plaques.

    METHODS AND RESULTS:

    Real time RTPCR showed that, of the nine different ADAMTS members examined, only ADAMTS-4 and -8 were induced during monocyte to macrophage differentiation, which was also seen at protein level. Macrophage expression of ADAMTS-4, -7, -8 and -9 mRNA were enhanced upon stimulation with IFN-gamma or TNF-alpha. Furthermore, immunohistochemical analyses revealed that ADAMTS-4 and -8 were expressed in macrophage rich areas of human atherosclerotic carotid plaques and coronary unstable plaques. In addition, ADAMTS-4 expression was upregulated during the development of atherosclerosis in LDLR(-/-)ApoB(100/100) mice. Whereas ADAMTS-4 expression was low in non-atherosclerotic aortas, it was significantly higher in aortas from 30-40-week old atherosclerotic animals.

    CONCLUSION:

    The present study suggests that ADAMTS-4 and -8 are inflammatory regulated enzymes expressed in macrophage-rich areas of atherosclerotic plaques. This is the first study associating ADAMTS-4 and -8 expression with atherosclerosis. However, further experiments are required to understand the physiological and pathological functions of ADAMTS in the vascular wall, and tools to measure ADAMTS activity need to be developed.

  • 41.
    Wågsäter, Dick
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Dienus, Olaf
    Ryhov County Hospital, Jönköping, Sweden .
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden .
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden .
    Dimberg, Jan
    University College of Health Sciences, Jönköping, Sweden.
    Quantification of the chemokines CCL17 and CCL22 in human colorectal adenocarcinomas2008In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 1, no 2, p. 211-217Article in journal (Refereed)
    Abstract [en]

    Chemokines are believed to play a crucial role in local immunoresponse by regulating leukocyte movement in various tissues, including the intestinal mucosa. It has been suggested that they are key players in cancer biology, and several studies have identified leukocyte infiltration as a hallmark of most cancers. The chemokines CCL17 and CCL22 attract CCR4-bearing cells, which are especially polarised to Th2-type cells and regulatory T cells (Treg). Recent studies have revealed the participation of the CCL17 and CCL22 proteins in diseases such as atopic dermatitis and lymphoma. The purpose of this study was to assess the role of CCL17 and CCL22 protein expression in colorectal cancer (CRC) and to ascertain whether an association exists between promoter -431Cgreater thanT CCL17 and -961Ggreater thanA CCL22 gene polymorphisms in CRC versus non-CRC subjects. Using the ELISA assay, we noted a significantly higher expression of CCL22 in tumour tissue with a 2.3-fold up-regulation (tumour vs. paired normal tissue, n=78) but no significant difference in CCL17 protein expression. Immunohistochemistry revealed protein expression of CCL22 and CCL17 in the epithelial compartment of cancer tissue, in epithelial cells at the resection border that reflects normal tissue, and in some stromal cells such as lymphocytes, macrophages, and fibroblasts. Using a TaqMan system we screened for -431Cgreater thanT CCL17 and -961Ggreater thanA CCL22 gene variants in 245 CRC patients and 256 controls, but could not find any significant difference in genotype distribution or in allelic frequencies between the two groups. The genotype and allelic distributions of CRC patients were not related to tissue levels of CCL17 and CCL22 protein, and none of the variables were associated with plasma levels or clinical characteristics. To ascertain whether the tissue expression of CCL17 and CCL22 exerts an influence oil the pathogenesis of CRC, a forthcoming study oil the 5-year survival rate of CRC patients will be conducted.

  • 42.
    Wågsäter, Dick
    et al.
    University of Örebro, Sweden .
    Dimberg, Jan
    University College of Health Sciences, Jönköping, Sweden.
    Expression of chemokine receptor CXCR6 in human colorectal adenocarcinomas2004In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 24, no 6, p. 3711-3714Article in journal (Refereed)
    Abstract [en]

    Infiltration of inflammatory cells into colorectal adenocarcinonzas is considered of importance for tumour progression. Tumour-associated macrophages and T cells are predominant components of the chemokine-guided filtrate of most colorectal tumours. CXCR6 is a chemokine receptor expressed by Th1, Tc, NKT cells and smooth muscle cells. To determine whether CXCR6 is expressed in human colorecial cancer and corresponding normal tissue, we analysed CXCR6 protein expression in 32 surgical specimens. Immunohistochemistry revealed CXCR6 protein predominantly; localised in normal epithelial cells and some scattered stromal cells. No or weak expression was found in cancerous tissue. Western blot analysis showed, in 41 % of the cases, a notable suppression of CXCR6 protein (13less than0.05) in cancerous tissue compared with non-cancerous tissue. Up-regulation was found in 9% of the cases. CXCR6 protein expression, in 25% of the cases, showed no difference between tumour, and adjacent normal tissue. Furthermore, 25% of the cases revealed undetectable levels of CXCR6 protein in tumour as well as corresponding normal tissue. The results may reflect one of the immunological features of normal and cancerous colorectal tissue and studies on regulation of CXCR6 are necessary in order to determine its role in colorectal carcinogenesis.

  • 43.
    Wågsäter, Dick
    et al.
    University of Örebro, Sweden .
    Dimberg, Jan
    Högskolan i Jönköping, Sweden.
    Hugander, Anders
    Länssjukhuset Ryhov, Jönköping, Sweden.
    Sirsjö, Allan
    University of Örebro, Sweden .
    Ghaderi, Mehran
    University of Örebro, Sweden .
    Analysis of MICA gene transcripts in human rectal cancers2003In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 23, no 3B, p. 2525-2529Article in journal (Refereed)
    Abstract [en]

    The human MHC class I chain-related gene A (MICA) encodes a protein which is an activator ligand for the NKG2D receptor on NK cells, CD8+ alphabeta T cells and gammadelta T cells. MICA expression is up-regulated upon cellular stress and its expression is correlated to infiltration of human NKG2D-bearing T cells into the tumors. It is assumed that the interaction of MICA-NKG2D ligand-receptor could play a significant role in induction of innate and adaptive responses against epithelial tumors, specifically those from the gastrointestinal tract. In this study MICA messenger RNA levels in human rectal carcinoma (Dukes stage B-D) and its normal adjacent tissue was analyzed in samples donated by 18 patients undergoing rectal tumor resection. Quantitative RTPCR analysis from rectal tumors revealed that the overall expression of MICA at mRNA level differs extensively among individual tumors. In addition, invasive rectal tumors tend to up-regulate MICA whereas MICA mRNA levels were lower in early tumors. Differential transcription levels of MICA gene expression in rectal carcinomas at different stages is probably a strategy by tumors to escape confrontation with intraepithelial tumor-infiltrating T cells.

  • 44.
    Wågsäter, Dick
    et al.
    University of Örebro, Sweden.
    Dimberg, Jan
    University of Örebro, Sweden.
    Sirsjö, Allan
    University of Örebro, Sweden.
    Induction of ATP-binding cassette A1 by all-trans retinoic acid: possible role of liver X receptor-alpha2003In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 11, no 4, p. 419-423Article in journal (Refereed)
    Abstract [en]

    ATP binding cassette A1 (ABCA1) is involved in the lipid metabolism of macrophages and has been suggested to play an important role in the development of foam cells and in the pathogenesis of atherosclerosis. We have investigated the effects of all-trans retinoic acid (atRA) on the mRNA and protein levels of ABCA1 in THP-1 cells. Our results show that both mRNA and protein levels of ABCA1 were significantly increased upon treatment with atRA. Since ABCA1 is highly regulated by liver X receptor (LXR) we also analysed the mRNA and protein expressions of LXR-alpha and LXR-6 in the THP-1 cells after treatment with atRA. Also the levels of LXR-alpha were increased by atRA. In conclusion, our results show that LXR-alpha and ABCA1 are simultaneously induced by atRA. The results also imply that the induction of ABCA1 by atRA may in part depend on the induction of LXR.

  • 45.
    Wågsäter, Dick
    et al.
    University of Örebro, Sweden.
    Hugander, Anders
    University of Örebro, Sweden .
    Dimberg, Jan
    University of Örebro, Sweden .
    Expression of CXCL16 in human rectal cancer2004In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 14, no 1, p. 65-69Article in journal (Refereed)
    Abstract [en]

    Local immunoregulation mediated by infiltration of inflammatory cells into colorectal adenocarcinomas is important for tumour progression. Tumour-associated macrophages and T cells are predominant components of chemokine-guided infiltrate of most colorectal tumours. CXCL16 is a newly discovered CXC chemokine expressed by antigen presenting cells attracting Th1, Tc and NK T cells. In this study, which is the first report on expression of the chemokine CXCL16 in human rectal cancer, CXCL16 gene and protein expression were analysed in cancer and normal adjacent tissue. Immunohistochemistry revealed CXCL16 expression in macrophages in normal tissue. The CXCL16 was found to a very limited extent in tumour-associated macrophages. Western blot analysis showed a suppression of CXCL16 protein in rectal cancer compared to non-cancer tissue in 83% of the patients (n=23, P=0.003). However, with real-time PCR mRNA was not down-regulated in the cancer compared to normal tissue, which may depend on regulated factor(s) at the level of translation and/or post-translation. The results may reflect one of the immunological mechanisms underlying carcinogenesis.

  • 46.
    Wågsäter, Dick
    et al.
    University of Örebro, Sweden.
    Jatta, Ken
    University of Örebro, Sweden.
    Ocaya, Pauline
    University of Örebro, Sweden.
    Dimberg, Jan
    University College of Health Sciences, Jönköping, Sweden.
    Sirsjö, Allan
    University of Örebro, Sweden.
    Expression of IL-1 beta, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: Effects of all-trans-retinoic acid2006In: Journal of Vascular Research, ISSN 1018-1172, E-ISSN 1423-0135, Vol. 43, no 4, p. 377-382Article in journal (Refereed)
    Abstract [en]

    The proinflammatory cytokine interleukin (IL)-1 beta and the IL-1 receptor antagonist are expressed by atherosclerotic plaques and may be linked to the development of atherosclerosis. Existing evidence shows that retinoids and their receptors are involved in inflammatory response and that they are found in atherosclerotic plaques. In all-trans-retinoic acid (atRA)-treated human aortic smooth muscle cells (AOSMC), significant increases in IL-1 beta levels were observed, compared with untreated cells. Examination of IL-1 receptor antagonist and IL-1 receptor type I levels did not show any difference between atRA-treated and -untreated AOSMC. The results show that atRA-treated AOSMC express both the precursor (33 kDa) and the active form (17 kDa) of the IL-1 P protein. atRA-treated carotid lesions showed significantly elevated IL-1 beta mRNA levels (2.9 +/- 2.33) compared with untreated lesions (2.0 +/- 1.77; p less than 0.05). These results support the role of atRA as a regulator of inflammation such as in atherosclerosis.

  • 47.
    Wågsäter, Dick
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Lofgren, Sture
    Ryhov County Hospital, Jönköping, Sweden.
    Zar, Niklas
    Ryhov County Hospital, Jönköping, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Dimberg, Jan
    University College of Health Sciences, Jönköping, Sweden.
    Pigment Epithelium-Derived Factor Expression in Colorectal Cancer Patients2010In: Cancer Investigation, ISSN 0735-7907, E-ISSN 1532-4192, Vol. 28, no 8, p. 872-877Article in journal (Refereed)
    Abstract [en]

    Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis and has been proposed to be a tumor suppressor in a variety of tumors. Limited reports exist of PEDF in colorectal cancer (CRC). We noted a 55% lower plasma level (p less than .001) of PEDF in the CRC patient group (1.6 mu g/mL) than in of a healthy control group (3.6 mu g/mL). A single nucleotide polymorphism (rs1136287, Tgreater thanC) was screened. In the control group, the CC genotype showed 30% lower PEDF plasma levels compared with the TT genotype (p less than .01), whereas the CRC patients failed to show any association regarding these genotypes.

  • 48.
    Wågsäter, Dick
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden.
    Hugander, Anders
    Ryhov County Hospital, Jönköping, Sweden.
    Dimberg, Jan
    University College of Health Sciences, Jönköping, Sweden.
    Expression of interleukin-17 in human colorectal cancer2006In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 26, no 6B, p. 4213-4216Article in journal (Refereed)
    Abstract [en]

    The proinflammatory cytokine IL-17 plays a potential role in T-cell mediated angiogenesis and promotes tumourigenicity of human cervical cancer. The objective of this study was to determine whether IL-17 protein level is altered in colorectal tumours (n=74) compared with paired normal mucosa and in plasma from patients (n=61) with colorectal cancer (CRC) compared with a healthy group (n=78). Analyses by ELISA showed that IL-17 protein was undetectable in 48.6% of the patients with cancer, as well as corresponding normal tissue which may in part reflect an individual difference. No significant difference was observed regarding IL-17 protein levels between cancer and matched normal tissue or in plasma between patients and the healthy group. Immunohistochemistry (n=20) revealed heterogenous immunoreactivity in 65% of the cases. The results of this study suggest that IL-17 plays a minor or partial role in CRC.

  • 49.
    Wågsäter, Dick
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Mumtaz, Melad
    Al-Nahrain University, Baghdad, Iraq.
    Löfgren, Sture
    Ryhov County Hospital, Jönköping, Sweden .
    Hugander, Anders
    University College of Health Sciences, Jönköping, Sweden.
    Dimberg, Jan
    Ryhov County Hospital, Jönköping, Sweden .
    Resistin in Human Colorectal Cancer: Increased Expression Independently of Resistin Promoter −420C > G genotype2008In: Cancer Investigation, ISSN 0735-7907, E-ISSN 1532-4192, Vol. 26, no 10, p. 1008-1014Article in journal (Refereed)
    Abstract [en]

    A single nucleotide polymorphism (SNP) -420Cgreater than G of the resistin gene was screened in 248 colorectal cancer (CRC) patients and 256 controls. No significant difference in genotype distribution was found. However, we found an upregulation in 92% of the samples in the levels of resistin protein in cancer tissue (n = 83). Immunohistochemical analysis revealed heterogenous staining of resistin predominantly in the cancer tissue. Further, resistin induced secretion of MMP-2 and MMP-9 from monocytes. The results of this study suggest that resistin may play a partial role in CRC but that the -420Cgreater than G resistin polymorphism is not a potential genetic susceptibility factor.

  • 50.
    Wågsäter, Dick
    et al.
    University of Örebro, Sweden.
    Olofsson, Peder S.
    Karolinska Hospital, Stockholm, Sweden.
    Norgren, Lars
    Örebro University Hospital, Sweden.
    Stenberg, Björn
    Örebro University Hospital, Sweden.
    Sirsjö, Allan
    University of Örebro, Sweden .
    The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon γ2004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 325, no 4, p. 1187-1193Article in journal (Refereed)
    Abstract [en]

    Atherosclerosis is an inflammatory disease that is characterised by the involvement of chemokines that are important for the recruitment of leukocytes and scavenger receptors that mediate foam cell formation. Several cytokines are involved in the regulation of chemokines and scavenger receptors in atherosclerosis. CXCL16 is a chemokine and scavenger receptor and found in macrophages in human atherosclerotic lesions. Using double-labelled immunohistochemistry, we identified that smooth muscle cells in human lesions express CXCL16. We then analysed the effects of IFN-gamma, TNF-alpha, IL-12, IL-15, IL-18, and LPS on CXCL16 expression in cultured aortic smooth muscle cells. IFN-gamma was the most potent CXCL16 inducer and increased mRNA, soluble form, membrane form, and total cellular levels of CXCL16. The IFN-gamma induction of CXCL16 was also associated with increased uptake of oxLDL into these cells. Taken together, smooth muscle cells express CXCL16 in atherosclerotic lesions, which may play a role in the attraction of T cells to atherosclerotic lesions and contribute to the cellular internalisation of modified LDL. (C) 2004 Elsevier Inc. All rights reserved.

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