Objective-Atherogenesis represents a type of chronic inflammation and involves elements of the immune response, eg, the expression of proinflammatory cytokines. In advanced atherosclerotic lesions, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is expressed in endothelial cells, macrophages, and smooth muscle cells (SMCs). In vitro, the expression of LOX-1 is induced by inflammatory cytokines like TNF-␣ and transforming growth factor (TGF)-␤. Therefore, LOX-1 is thought to be upregulated locally in response to cytokines in vivo. Methods and Results-We determined by reverse-transcription polymerase chain reaction (PCR) and Western blot analysis whether the mediators of the acute phase response in inflammation, IL-1␣, IL-1␤, and TNF-␣, regulate LOX-1 expression in cultured SMC, and whether this regulation is influenced by peroxisome proliferator-activated receptor ␥ (PPAR␥). We studied by immunohistochemistry whether these cytokines are spatially correlated with LOX-1 expression in advanced atherosclerotic lesions. We found upregulation of LOX-1 expression in SMC in a dose-and time-dependent manner after incubation with IL-1␣, IL-1␤, and TNF-␣. Simultaneous incubation with these cytokines at saturated concentrations had an additive effect on LOX-1 expression. The PPAR␥ activator, 15d-PGJ 2 , however, inhibited IL-1␤-induced upregulation of LOX-1. In the intima of atherosclerotic lesions regions of IL-1␣, IL-1␤, and TNF-␣ expression corresponded to regions of LOX-1 expression. Conclusion-We suppose that upregulated LOX-1 expression in SMC of advanced atherosclerotic lesions is a response to these proinflammatory cytokines. Moreover, the proinflammatory effects of these cytokines can be decreased by the antiinflammatory effect of PPAR␥.

The expression of the IL6 receptor components in the donor heart before transplantation establishes the condition sine qua non for the response of the donor heart to circulating IL6. This mechanism may explain the close association of elevated IL6 serum levels to acute cardiac allograft dysfunction in the early perioperative period.

Background-LOX-1, a receptor for oxidized low-density lipoprotein (OxLDL), seems to play a critical role in foam cell formation of macrophages (Ms) and smooth muscle cells (SMC). Inhibition of LOX-1 expression reduces foam cell formation and might influence lipid core formation in atherosclerotic lesions. Because statins are able to downregulate LOX-1 expression in vitro, we examined if pravastatin can be used to reduce LOX-1 expression and lipid core formation in lesions of Watanabe heritable hyperlipidemic (WHHL) rabbits. Methods and Results-Pravastatin downregulated LOX-1 expression in cultured human Ms and in cultured human aorticSMCs. Homozygous WHHL rabbits were treated with 50 mg kg Ϫ1 d Ϫ1 pravastatin for 32 weeks. Immunohistochemical studies revealed that LOX-1 was expressed in intimal Ms and SMCs of atherosclerotic lesions. The pravastatin-treated rabbits showed, compared with untreated rabbits, a significantly reduced LOX-1 protein and mRNA expression in the aortic arch. Lipid labeling of this aorta region also demonstrated a strong reduction of the ratio of lipid core area/total lesion area in pravastatin-treated rabbits. The cellular uptake of OxLDL is mediated by so-called scavenger receptors, a heterogenous family of membrane bound proteins. 1 Among them, the receptor LOX-1 is expressed in macrophages (Ms) and smooth muscle cells (SMCs) in the intima of atherosclerotic lesions. 2 Foam cells derive from Ms and SMCs and have been implicated in the formation of the lipid core. Therefore, a role of LOX-1 in foam cell formation has been suggested, and downregulation of LOX-1 could in theory reduce the lipid core development by inhibition of foam cell formation. Conclusions-The in vivo inhibitionSeveral authors have reported downregulation of LOX-1 expression in cultured cells in response to different stimuli. For example, upregulation of LOX-1 expression by angiotensin II can be inhibited by means of the angiotensin II type 1 receptor blocker losartan in endothelial cells (ECs). 3,4 Upregulation of LOX-1 expression by tumor necrosis factor (TNF)-␣ and IL-1␤ is inhibited by peroxisome proliferatoractivated receptor-␥ (PPAR-␥) activators in SMCs and ECs. 5,6 Furthermore, Chen et al (2000) showed that losartan decreased LOX-1 expression in cultured cells and also in the neointima of rabbits. 7 Lipid-lowering 3-hydroxy-3-methyl glutaryl coenzyme A (CoA) (3-hydroxy-3-methylglutaryl [HMG]-CoA) reductase inhibitors (statins) are also known to downregulate LOX-1. In cultured M lovastatin inhibits LOX-1 expression in cultured Ms. 8 Li et al (2001) reported downregulation of LOX-1 expression and reduced uptake of OxLDL in EC after incubation with simvastatin and atorvastatin. 9 It is known that statins are potent agents for lowering total and low-density lipoprotein cholesterol. Clinical trials have demonstrated that these agents are able to reduce the incidence of cardiovascular diseases. Until now, no in vivo data on the influence of statins on LOX-1 expression in the vessel wall were available. Therefore, w...

Our results show that PKC delta is required for the bFGF-stimulated c-Raf1-MEK-MAPK-c-myc signaling pathway involved in the proliferation of cSMC. Therefore, it may be an interesting therapeutic target for preventing proliferative vascular disorders.

GM-CSF takes part in the cytokine network regulating the metabolism of extracellular matrix (ECM) during atherogenesis. Since data also point to an effect of GM-CSF on the vascular ECM in general, the vascular collagenous matrix was studied in wild-type and GM-CSF-deficient mice. Histological examination revealed a disorganized vascular ECM in GM-CSF-deficient mice involving the collagenous matrix and elastic fiber system. As shown by electron microscopy, collagen bundles were disrupted and reduced. The diameter of fibrils varied widely. mRNA expression of collagens and related molecules was studied. Fibrillar collagens were markedly reduced, alpha1(I)procollagen to 16.5% of control levels alpha1(III)procollagen was abolished whereas the expression level of network-forming alpha1(VIII)procollagen was not altered. As shown by in situ hybridization, the number of collagen-expressing cells was reduced. Matrix metalloproteinases and their inhibitor 1 were not affected by GM-CSF deficiency. Our studies demonstrate that GM-CSF plays a major role in the cytokine network regulating the metabolism of vascular collagens. GM-CSF deficiency leads to an altered composition of the vascular collagenous matrix, i.e., reduced amount of fibrillar collagen, altered ratio of fibrillar and network-forming collagen, and failures in the fibrillogenesis. We suggest that GM-CSF is a basic requirement for the maintenance of vessel wall integrity and resilience.

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Background: Granulocyte macrophage colony-stimulating factor (GM-CSF) deficiency affects the production and fiber assembly/organization of the vascular collagenous matrix; structural alterations to the elastic system were observed. The present study elaborates the effect of GM-CSF deficiency on the vascular elastin system. Methods and Results: Histological examination of the aorta of GM-CSF-deficient mice revealed structurally altered elastic fibers. The elastic fiber area was significantly enhanced, whereas the remaining medial area was not affected. Aortic size was significantly increased. Reverse transcription polymerase chain reaction demonstrated decreased expression levels of tropoelastin, lysyl oxidase and bone morphogenetic protein 1 (BMP-1). Cell culture studies on vascular smooth muscle cells showed that after clearance of GM-CSF with GM-CSF antibodies, the tropoelastin mRNA expression was markedly reduced. Concomitantly, lysyl oxidase and BMP-1 mRNA levels were decreased. Treatment with GM-CSF stimulated the expression of these mRNAs. Conclusions: Our studies demonstrate that disorganization of elastic lamellae as induced by GM-CSF deficiency is associated with adaptive vascular remodeling. The decreased tropoelastin expression observed is associated with elastic fiber hypertrophy. This paradox effect may be explained by decreased expression levels of lysyl oxidase and BMP-1, both mediating cross-linkage and thus assembly and organization of elastic fibers. From our data, we conclude that GM-CSF is a prerequisite for the maintenance of structural integrity of the vessel wall.

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