| 1. |
- Olofsson, Peder S., et al.
(författare)
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CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice
- 2008
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Ingår i: Circulation. - Baltimore, Md. : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 117:10, s. 1292-1301
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Tidskriftsartikel (refereegranskat)abstract
- 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-Ab 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.
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| 2. |
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| 3. |
- Sheikine, Yuri, et al.
(författare)
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Activation of VPAC(1) receptors aggravates early atherosclerosis in hypercholesterolemic apolipoprotein E-deficient mice
- 2010
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier Science B.V., Amsterdam. - 0006-291X .- 1090-2104. ; 402:3, s. 471-476
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Tidskriftsartikel (refereegranskat)abstract
- Objective Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide widely expressed in the body and binding three types of receptors VPAC(1)-R, VPAC(2)-R and PAC(1)-R Based on beneficial effects of VIP and VPAC(1)-R agonists in mouse models of several chronic inflammatory disorders, we hypothesized that activation of VIP receptors would prevent atherosclerosis development in apolipoprotein E-deficient mice Methods and results Contrary to our hypothesis, administration of a VPAC(1)-R agonist. (Ala(11 22,28))-VIP aggravated atherosclerotic lesion development in the aortic root of these mice compared to control mice This was accompanied by a significant Increase in the expression of MHC class II protein I-A(b), and suggests enhanced inflammatory activity in the vessel wall The amount of macrophage-specific CD68 staining as well as serum cholesterol and triglyceride levels did not change as a result of the (Ala(11 22,28))-VIP treatment, i e the treatment resulted in significant changes in lipid accumulation in the lesions without changing the number of macrophages or systemic lipid levels Interestingly, administration of VIP did not alter the course of the disease. Conclusion: Despite beneficial effects in murine models of several inflammatory disorders, VPAC(1)-R activation aggravates atherosclerotic lesion formation in apolipoprotein E-deficient mice through enhanced inflammatory activity in the vessel wall
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| 4. |
- Sheikine, Yuri
(författare)
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Chemoattractants as causative agents, biomarkers and therapeutic targets in vascular pathology
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atherosclerosis and restenosis are driven by chronic immune response in the vascular wall. This involves cell migration into and within the vessel wall, cell proliferation as well as accumulation of lipids in the vessel wall. These processes are mediated, among other substances, by molecules belonging to a large family of chemoattractants. The aim of this thesis was to investigate whether several chemoattractants can serve as causative agents, biomarkers and therapeutic targets in atherosclerosis and restenosis. One of the recently discovered chemoattractants, chemokine CXCL16 exists in soluble and transmembrane forms. It ligates chemokine receptor CXCR6 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 (oxLDL) by cells. We detected abundant CXCL16/SR-PSOX and CXCR6 expression in atherosclerotic lesions from human subjects and apolipoprotein-Edeficient (ApoE-/-) mice. In monocytes, CXCL16/SR-PSOX expression was increased by interferon-γ (IFN-γ), a proatherogenic cytokine abundant in atherosclerotic lesions. This corresponded to increased uptake of oxLDL by monocytes, which was specifically mediated by CXCL16/SR-PSOX. IFN-γ injections to ApoE-/- mice induced CXCL16/SR-PSOX expression in atherosclerotic lesions. These data demonstrate a novel role of IFN-γ in cellular lipid accumulation through up-regulation of CXCL16/SR-PSOX and suggest that CXCL16/SR-PSOX may serve as a molecular link between lipid metabolism and immune activity in the atherosclerotic lesion. These results also suggested that patients with atherosclerosis may present with altered levels of CXCL16/SR-PSOX in the systemic circulation. Using ELISA we assessed plasma CXCL16/SR-PSOX concentration in stable angina pectoris (SAP) patients, unstable angina pectoris/non-ST-elevation myocardial infarction (UAP/non-STEMI) patients, survivors of a first myocardial infarction (MI) and healthy control subjects. SAP patients exhibited significantly lower median CXCL16/SR-PSOX levels than control subjects, while UAP/non-STEMI patients and post-MI patients tended to have lower CXCL16/SR-PSOX levels compared to controls. At the same time there were no significant correlations between CXCL16/SR-PSOX levels and measures of coronary artery disease (CAD) severity: angiographically determined degree of coronary artery stenosis, plasma lipoprotein fractions, inflammatory cytokines and C-reactive protein. The finding that lower plasma CXCL16/SR-PSOX concentration is associated with CAD might indicate a potential atheroprotective function of CXCL16/SR-PSOX and suggests that it is worth further investigation as a CAD biomarker. CCL11 (eotaxin) is another chemokine, whose systemic levels and genetic variants might be associated with CAD. However, the relationship between CCL11 genetic variants and plasma concentrations in CAD patients has not been studied. We genotyped post-MI patients and healthy controls for a 67G>A single nucleotide polymorphism (SNP) in the CCL11 gene and related the presence of the former to the plasma CCL11 concentrations, measured by ELISA. There were no differences in CCL1 genotype frequencies between patients and controls. Patient G/G carriers had higher circulating CCL11 levels compared both to G/A and A/A patients and G/G controls. At the same time, CCL11 levels did not differ between patients and controls irrespective of the 67G>A SNP variants they carried. No associations were found between plasma CCL11 levels and biochemical indicators of CAD or the degree of coronary artery stenosis in patients. Taken together, we show that despite certain influence of 67G>A SNP on CCL11 plasma levels, neither of them is useful for distinguishing subjects with and without clinical manifestations of coronary atherosclerosis. Leukotriene B4 (LTB4), a potent chemoattractant derived from arachidonic acid, exerts its action by means of specific receptors BLT1 and BLT2. In this study, BLT1 protein was detected in human atherosclerotic plaques, where it colocalized with macrophages, endothelial cells, and smooth muscle cells (SMC). Human coronary artery SMC exposed to either the LTB4 Or the BLT1 partial agonist U75302 exhibited increase of whole-cell ion currents indicating that these cells express functional BLT1 LTB4 induced BLT1-mediated migration and proliferation of SMC in vitro, while treatment with the BLT1 antagonist BIIL284 inhibited balloon injury-induced carotid artery neointimal hyperplasia in rats. In the latter model, intimal SMC exhibited increased expression of BLT1 compared with medial SMC. This could be prevented by transfection with a dominant-negative form Of IκB kinase-β, indicating that BLT1 expression depends on NF-κB. These results show that LTB4 activates functional BLT1 on vascular SMC affecting their chemotaxis and proliferation, and that inhibition of BLT1 signaling reduces neointimal hyperplasia, suggesting this pathway as a possible target for restenosis therapy. In summary, this thesis suggests the novel roles for such chemoattractants as CXCL16/SR-PSOX and LTB4 in the development of atherosclerosis and restenosis, respectively. Moreover, CXCL16/SR-PSOX deserves further investigation as a CAD biomarker, while CCL11 is unlikely to be validated as such. And finally, therapy directed at LTB4/BLT1 axis may be useful for the treatment of post-angioplasty restenosis.
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| 5. |
- Sheikine, Yuri, et al.
(författare)
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CXCL16/SR-PSOX : a friend or a foe in atherosclerosis?
- 2008
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Ingår i: Atherosclerosis. - Amsterdam : Elsevier. - 0021-9150 .- 1879-1484. ; 197:2, s. 487-495
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Forskningsöversikt (refereegranskat)abstract
- Chemokines, scavenger receptors and adhesion molecules have long been known as important players in the pathogenesis of atherosclerosis. A series of studies conducted in the past few years described CXCL16/SR-PSOX—a new molecule combining those three functions, and suggested that CXCL16/SR-PSOX can be a potential player in atherogenesis. Initial ex vivo studies showed that CXCL16/SR-PSOX is abundant in human and murine atherosclerotic lesions. Following in vitro studies suggested that as an adhesion molecule CXCL16/SR-PSOX might mediate T-cell adhesion to the endothelium, as a chemokine – drive T-cell migration, stimulate cell proliferation and elicit inflammatory phenotype in smooth muscle cells (SMC) and, finally, as a scavenger receptor – mediate uptake of atherogenic lipoproteins by macrophages and SMC. All these effects are known to be pro-atherogenic. Surprisingly, in vivo studies performed in murine models of atherosclerosis suggested that CXCL16/SR-PSOX is atheroprotective, while its receptor CXCR6 is harmful. In addition, studies investigating the association of circulating CXCL16/SR-PSOX plasma concentrations with the presence and extent of coronary artery disease (CAD) in humans are controversial suggesting both positive, negative and no association. To finally answer the question whether CXCL16/SR-PSOX can serve as a causative factor, biomarker or even a therapeutic target in atherosclerosis, we are currently in need of carefully designed animal and human studies investigating the effects of CXCL16/SR-PSOX and CXCR6 deficiency, inhibition and over-expression on the progression of atherosclerosis. Such complex approach will help us unravel the mystery of CXCL16/SR-PSOX in atherosclerosis and hopefully develop better ways of treating atherosclerosis by targeting this interesting molecule.
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| 6. |
- Wuttge, Dirk M., et al.
(författare)
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CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions
- 2004
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 24:4, s. 750-755
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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