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Objective : The scavenger receptor SR-PSOX/CXCL16, which is identical to the chemokine CXCL16, is thought to be involved in atherogenesis. However, the presence and function of SR-PSOX/CXCL16 in the endothelium of atherosclerotic arteries has not been substantiated. Methods and results : In rabbit aorta immunocytochemistry revealed SR-PSOX/CXCL16 primarily in the endothelium at sites predisposed to lesion formation, in the endothelium of early atherosclerotic lesions, and mainly in intimal macrophages of more developed lesions, indicating that SR-PSOX/CXCL16-expression shifts during atherogenesis. In addition to its function as scavenger receptor and chemokine, SR-PSOX mediated the adhesion of THP-1 monocytes to endothelial cells in vitro. Both THP-1 monocytes and endothelial cells express SR-PSOX/CXCL16, and THP-1 monocytes express CXCR6, the specific receptor for SR-PSOX/CXCL16. Anti-SR-PSOX/CXCL16 and anti-CXCR6 antibody block monocyte adhesion, showing that SR-PSOX/CXCL16–CXCR6 interaction mediates monocyte-endothelial cell adhesion. SR-PSOX/CXCL16 expression of endothelial cells is upregulated by pro-inflammatory cytokines, and is reversed by incubation with ciglitazone and lovastatin. Conclusions : We suggest that SR-PSOX/CXCL16 may promote the adhesion of monocytes to the endothelium during early atherogenesis and that accumulating cytokines enhance SR-PSOX/CXCL16-mediated adhesion by upregulating SR-PSOX/CXCL16 expression. Manipulation of SR-PSOX/CXCL16 expression with anti-inflammatory agents may be of therapeutic value.

Objectives HIGH-density lipoproteins (HDL) are a negative predictor of platelet-dependent thrombus formation and reduced platelet activation has been observed in vitro in the presence of HDL3, a major HDL fraction. However, mechanisms underlying the anti-thrombotic effects of HDL3 are poorly understood. Scavenger receptors class B represent possible HDL3 binding partners on platelets. We here investigated the role of scavenger receptor class B type I (SR-BI) and CD36 in mediating inhibitory effects of native HDL3 on thrombin-induced platelet activation. Methods and results Rhodamine isothiocyanate-labeled HDL3 bound specifically to platelets and HDL3 binding was inhibited by scavenger receptor class B ligands such as phosphatidylserine (PS)- or phosphatidylinositol (PI)-containing liposomes or maleylated albumin (mBSA). By contrast, scavenger receptor class A ligands failed to displace HDL3 from platelets. HDL3, PS- and PI-liposomes, and mBSA inhibited thrombin-induced platelet aggregation, fibrinogen binding, P-selectin expression and mobilization of intracellular Ca 2+ . In addition, PS- and PI-liposomes emulated HDL3-induced intracellular signaling cascades including diacylglycerol production and protein kinase C activation. The reduction of platelet activation by liposomes was related to their PS or PI content. Moreover, inhibitory effects of native HDL3 were enhanced after enriching lipoproteins with PS, while PS- and PI-poor HDL2 failed to inhibit platelet aggregation and Ca 2+ mobilization. Both, HDL3 and PS-containing liposomes failed to inhibit thrombin-induced activation of platelets obtained from SR-BI-deficient mice but not CD36-deficient mice. Conclusion We suggest that SR-BI is a functional receptor for native HDL3 on platelets that generates an inhibitory signal for platelet activation. The content of negatively charged phospholipids (PS, PI) in HDL may be an important determinant of their anti-thrombotic potential.

Collagens play a central role in maintaining the integrity and stability of the undiseased as well as of the atherosclerotic vessel wall. An imbalanced metabolism may lead to uncontrolled collagen accumulation reducing vessel wall velocity, frequently resulting in arterial occlusion or thrombosis. A reduced production of collagen and its uncontrolled degradation may affect the stability of the vessel wall and especially of the atherosclerotic plaques by making them prone to rupture and aneurysm. This review presents an overview on the four groups of vascular collagens and on their role in atherogenesis. The major focus was to highlight the extraordinary role and importance of the short chain network forming type VIII collagen in the extracellular matrix of undiseased arteries and of atherosclerotic plaques. The molecular structure of type VIII collagen, its cellular origin, its implication in atherogenesis, its temporal and spatial expression patterns in human and experimental models of atherogenesis, the factors modulating its expression, and—not at least—its potential function is discussed.

Colony stimulating factors belong to a family of cytokines that regulate proliferation in macrophages and other vascular cell types. They have been implicated in the inflammatory-fibroproliferative response of atherosclerosis. The present study was undertaken to assess the effect of granulocyte-macrophage and macrophage colony stimulating factors on the transcription of type VIII collagen by vascular smooth muscle cells and their potential relevance for the expression of collagen in atherosclerotic lesions. The influence of colony stimulating factors was studied in relation to transforming growth factor beta1, the factor exhibiting the most potent effect on collagen metabolism. Northern blot experiments showed that treatment with both colony stimulating factors and transforming growth factor beta1 transiently stimulated the transcription of type VIII collagen mRNA. Maximal levels were reached after 2 h and 100 pg/ml granulocyte macrophage colony stimulating factor (4-fold), 1 U/ml macrophage colony stimulating factor (4.6-fold) and 1 ng/ml transforming growth factor beta1 (1.6-fold). While overnight treatment with colony stimulating factors stimulated the expression of transforming growth factor beta1 mRNA, short incubations did not influence or downregulate the transcription. In turn, treatment with transforming growth factor beta1 reduced the expression of granulocyte-macrophage and macrophage colony stimulating factor mRNA. The in vitro mRNA expression patterns were directly reflected in the distribution patterns found in intimal thickenings and advanced atherosclerotic lesions. This study demonstrates that colony stimulating factors and transforming growth factor beta1 modulate the transcription of type VIII collagen in vitro. Our data indicate a direct mechanism and exclude a pathway, which is mediated via the stimulation of transforming growth factor beta1 transcription. Our studies further support the hypothesis that colony stimulating factors in concert with transforming growth factor beta1 affect the collagenous composition of the extracellular vascular matrix.

HIGH-density lipoproteins (HDL) are a negative predictor of platelet-dependent thrombus formation and reduced platelet activation has been observed in vitro in the presence of HDL3, a major HDL fraction. However, mechanisms underlying the anti-thrombotic effects of HDL3 are poorly understood. Scavenger receptors class B represent possible HDL3 binding partners on platelets. We here investigated the role of scavenger receptor class B type I (SR-BI) and CD36 in mediating inhibitory effects of native HDL3 on thrombin-induced platelet activation.Rhodamine isothiocyanate-labeled HDL3 bound specifically to platelets and HDL3 binding was inhibited by scavenger receptor class B ligands such as phosphatidylserine (PS)- or phosphatidylinositol (PI)-containing liposomes or maleylated albumin (mBSA). By contrast, scavenger receptor class A ligands failed to displace HDL3 from platelets. HDL3, PS- and PI-liposomes, and mBSA inhibited thrombin-induced platelet aggregation, fibrinogen binding, P-selectin expression and mobilization of intracellular Ca(2+). In addition, PS- and PI-liposomes emulated HDL3-induced intracellular signaling cascades including diacylglycerol production and protein kinase C activation. The reduction of platelet activation by liposomes was related to their PS or PI content. Moreover, inhibitory effects of native HDL3 were enhanced after enriching lipoproteins with PS, while PS- and PI-poor HDL2 failed to inhibit platelet aggregation and Ca(2+) mobilization. Both, HDL3 and PS-containing liposomes failed to inhibit thrombin-induced activation of platelets obtained from SR-BI-deficient mice but not CD36-deficient mice.We suggest that SR-BI is a functional receptor for native HDL3 on platelets that generates an inhibitory signal for platelet activation. The content of negatively charged phospholipids (PS, PI) in HDL may be an important determinant of their anti-thrombotic potential.

The pathogenesis of arteriosclerosis and of restenosis after angioplasty is linked with an inflammatory and fibroproliferative response of the arterial tissue. We have induced a non-infectious inflammation by implanting a silicon–copper cuff around rat carotid arteries. The copper ions released from the oxidized copper initiate and mimic all morphological features of post-angioplasty restenotic and arteriosclerotic lesions. The copper-induced lesions were analyzed by electron and light microscopy, immunohistochemical methods and quantified by morphometry. During the first phase of copper-induced tissue reaction (3 days), macrophages and polymorphonuclear leucocytes invaded through the endothelium, accumulated in the subendothelial space and triggered the proliferation of smooth muscle cells which then migrated from the tunica media through the lamina elastica interna into the intima. Within 3 weeks, the accumulated smooth muscle cells, macrophages, leucocytes and newly synthesized extracellular matrix formed a circular mostly eccentric fibrotic thickening that narrows the vessel lumen by 30–40%. The accompanying structural disorganization of the medial layer led to focal rupture and aneurysm-like dilatation of the vessel wall in 3 of 11 animals between day 20 and 43. The neointima progressively increased in thickness over time leading to corresponding reduction of the vessel lumen. The carotid arteries of control animals and animals treated with copper-free silicon cuffs showed no abnormal pathological appearence. Our results show that inflammation-inducing agents can contribute to and simulate restenosis- and arteriosclerosis-like lesions and that the copper-cuff model may be useful in the exploration of new approaches to intervention.