Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerotic plaques contain a significant number of macrophage foam cells and are associated with an inflammatory state. Inflammation induces the secretion from monocytes and other cells of cytokines, reactive oxygen species, proteinases and proteinase inhibitors among many other molecular species. AAT is prominent among the serine proteinase inhibitors and is an important regulator of leukocyte elastase and proteinase-3. It has been shown that the stable AAT-proteinase complex can upregulate AAT biosynthesis, and we have shown that the shorter, carboxyl terminal peptide (C-36) resulting from proteinase cleavage of AAT polymerizes, and in its fibrillar form alters cellular metabolism. To test for a possible link between the inflammation-generated C-36 peptide and cellular processes associated with atherogenesis, we have studied the effects of the fibrillar form of this peptide at varying concentrations on human monocytes in culture. We have found that fibrillar C-36 at concentrations of greater than or equal to 5 micromol/l in monocyte cultures for 24 h significantly increases LDL binding and uptake, upregulates LDL receptors, induces cytokine production and glutathione reductase activity, and upregulates AAT synthesis. The expression of CD36 protein, LDL Scavenger receptor, is also upregulated by fibrillar C-36 and native LDL in the presence of C-36-activated monocytes is more oxidized than with unactivated control monocytes. The majority of monocytes cultured for 24 h in the presence of C-36 fibrils were transformed morphologically into macrophages. These data establish a direct molecular link, mediated by C-36 peptide of AAT, between inflammation and the oxidation and accumulation of lipid in monocyte-derived macrophages. This may be important for an understanding of the events conducive to atherogenesis.
Atherosclerosis 1999 Dec
PMID:Atherogenic properties of human monocytes induced by the carboxyl terminal proteolytic fragment of alpha-1-antitrypsin. 1055 12

The transformation of monocyte-derived macrophages into lipid-laden foam cells constitutes a characteristic and crucial event in the development of the earliest atherosclerotic lesions. We investigated whether the propensity to form foam cells varies among individuals. We developed a fully autologous foam cell assay based on a recently developed novel culture technique for human monocyte-derived macrophages (Wintergerst ES, Jelk J, Asmis, R. Differential expression of CD14, CD36 and the LDL receptor on human monocyte-derived macrophages. A novel cell culture system to study macrophage differentiation and heterogeneity, Histochem. Cell Biol. 1998;110:231-241). Thin layer chromatography and laser densitometry were used to determine cholesterol, triglyceride and cholesteryl ester levels in human macrophages. Aggregated LDL obtained by vortexing was found to be a reproducible stimulus of foam cell formation in human macrophages. In our hands, Cu(2+)-oxidized LDL also induced cholesteryl ester accumulation, but only when vortexed. We found that foam cell formation in an individual varied by less than 25% over a 10-month period. In contrast, we observed a sevenfold difference in foam cell formation among eight male volunteers. The transfer of foam cells into culture medium with freshly thawed autologous serum resulted in a 75% regression within 1 week, independent of the amount of cellular cholesteryl esters accumulated. Foam cell formation correlated neither to serum nor to cellular cholesterol and triglyceride levels. The propensity to form foam cells could therefore represent a novel indicator of individual risk of atherogenesis.
Atherosclerosis 2000 Feb
PMID:Large variations in human foam cell formation in individuals: a fully autologous in vitro assay based on the quantitative analysis of cellular neutral lipids. 1065 59

The peroxisome-proliferator-activated receptor gamma is a member of the nuclear receptor superfamily that functions as a key transcriptional regulator of cell differentiation and lipid metabolism. In addition, peroxisome-proliferator-activated receptor gamma is now recognized to be the biological receptor for the thiazolidinedione class of antidiabetic drugs, which includes troglitazone and rosiglitazone. Recent evidence indicates that peroxisome-proliferator-activated receptor gamma is expressed at high levels in macrophages, including the foam cells of atherosclerotic lesions. Oxidized low-density lipoprotein, which plays a central role in lesion development, can activate peroxisome-proliferator-activated receptor gamma by providing the cell with oxidized fatty acid ligands of the receptor. The elucidation of a peroxisome-proliferator-activated receptor gamma signalling pathway in macrophages provides a mechanism by which oxidized lipids may directly regulate gene expression in the context of the atherosclerotic lesions. A number of potential target genes for peroxisome-proliferator-activated receptor gamma in these cells have been identified. Some, such as the type B scavenger receptor CD36 are induced by peroxisome-proliferator-activated receptor gamma ligands, whereas others, such as scavenger receptor type A, inducible nitric oxide synthetase and certain cytokines, are repressed. Given the widespread clinical use of thiazolidinediones, it is important to consider the influence of these drugs on the risk of atherosclerosis. The net effect of peroxisome-proliferator-activated receptor gamma ligands on the atherogenic process is likely to reflect a balance between local effects in the artery wall and systemic effects on lipid metabolism.
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PMID:Regulation of macrophage gene expression by peroxisome-proliferator-activated receptor gamma: implications for cardiovascular disease. 1068 41

Macrophage scavenger receptors have been implicated as key players in the pathogenesis of atherosclerosis. To assess the role of the class B scavenger receptor CD36 in atherogenesis, we crossed a CD36-null strain with the atherogenic apo E-null strain and quantified lesion development. There was a 76.5% decrease in aortic tree lesion area (Western diet) and a 45% decrease in aortic sinus lesion area (normal chow) in the CD36-apo E double-null mice when compared with controls, despite alterations in lipoprotein profiles that often correlate with increased atherogenicity. Macrophages derived from CD36-apo E double-null mice bound and internalized more than 60% less copper-oxidized LDL and LDL modified by monocyte-generated reactive nitrogen species. A similar inhibition of in vitro lipid accumulation and foam cell formation after exposure to these ligands was seen. These results support a major role for CD36 in atherosclerotic lesion development in vivo and suggest that blockade of CD36 can be protective even in more extreme proatherogenic circumstances.
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PMID:Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. 1097 14

Lectin-like oxidized low-density lipoprotein (Ox-LDL) receptor-1 (LOX-1) is a novel cell-surface receptor for Ox-LDL, which can be expressed by vascular endothelial cells, smooth muscle cells, and macrophages. On the other hand, transforming growth factor (TGF)-beta(1), which plays crucial roles in vascular remodeling and the pathogenesis of atherosclerosis, has been shown to inhibit expression of class A scavenger receptors and CD36 in macrophages. Here we provide the evidence that TGF-beta(1) (0.1-10 ng/mL) induces LOX-1 protein and mRNA expression in both bovine aortic endothelial cells and smooth muscle cells in a dose- and time-dependent fashion, probably at the transcriptional level. TGF-beta(1) also upregulates LOX-1 mRNA expression in murine peritoneal macrophages. Thus TGF-beta(1) can highly induce LOX-1 expression in vascular endothelial cells, smooth muscle cells, and macrophages, suggesting that TGF-beta(1) appears one of the key regulators that modulates expression of scavenger receptors.
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PMID:Transforming growth factor-beta(1) increases the expression of lectin-like oxidized low-density lipoprotein receptor-1. 1083 18

CD36, an 88 kD transmembrane glycoprotein, is an important receptor for oxidized lipoproteins. Unlike the LDL receptor, expression of CD36 is upregulated by this pro-atherogenic particle, and binding and uptake perpetuates a cycle of lipid accumulation and receptor expression. This effect is, in part, mediated by the transcription factor, peroxisome proliferator activated receptor-gamma (PPAR gamma), and its ligands. We have found that specific inhibitors of protein kinase C (PKC) reduce basal mRNA expression of CD36 and block induction of CD36 mRNA and protein by oxidized LDL (OxLDL) and a PPAR gamma ligand. In addition, PKC inhibitors block both PPAR gamma mRNA and protein expression. These results suggest that activation of CD36 gene expression by OxLDL involves activation and translocation of PKC with subsequent PPAR gamma activation. More recently, we have generated a mouse null for CD36, and crossed it with the atherogenic Apo E null strain. Evaluation of lesion development in these animals will allow us to assess the in vivo contribution of CD36 to the pathogenesis of atherosclerosis.
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PMID:CD36 in atherosclerosis. The role of a class B macrophage scavenger receptor. 1086 32

Angiotensin II (Ang II) and oxidized LDL (Ox-LDL) are risk factors for atherosclerosis, and both of them contribute to macrophage cholesterol accumulation, the hallmark of early atherosclerosis. As Ang II was shown to increase macrophage uptake of Ox-LDL, we investigated the effect of losartan, an Ang II receptor antagonist with antiatherogenic properties, on the cellular uptake of Ox-LDL by human monocyte-derived macrophages (HMDM) from hypercholesterolemic patients. Eight normotensive hypercholesterolemic patients were treated with losartan (50 mg/day) for a period of 4 weeks. Losartan therapy did not significantly affect the degradation of native LDL by the patients' HMDM. However, losartan therapy significantly reduced HMDM uptake of Ox-LDL as shown by a 78% reduction in Ox-LDL cell-association and a 21% reduction in Ox-LDL degradation. CD36 (an Ox-LDL receptor) mRNA expression in HMDM obtained after losartan treatment was decreased by 54% compared to HMDM obtained before treatment. The ability of losartan to inhibit HMDM CD36 mRNA expression and, hence, Ox-LDL uptake and macrophage foam cell formation is probably related to the blockage of Ang II binding to the cell surface and thus to the prevention of Ang II atherogenic effects.
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PMID:Losartan inhibits cellular uptake of oxidized LDL by monocyte-macrophages from hypercholesterolemic patients. 1087 20

The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that regulates fat-cell development and glucose homeostasis and is the molecular target of a class of insulin-sensitizing agents used for the management of type 2 diabetes mellitus. PPARgamma is highly expressed in macrophage foam cells of atherosclerotic lesions and has been demonstrated in cultured macrophages to both positively and negatively regulate genes implicated in the development of atherosclerosis. We report here that the PPARgamma-specific agonists rosiglitazone and GW7845 strongly inhibited the development of atherosclerosis in LDL receptor-deficient male mice, despite increased expression of the CD36 scavenger receptor in the arterial wall. The antiatherogenic effect in male mice was correlated with improved insulin sensitivity and decreased tissue expression of TNF-alpha and gelatinase B, indicating both systemic and local actions of PPARgamma. These findings suggest that PPARgamma agonists may exert antiatherogenic effects in diabetic patients and provide impetus for efforts to develop PPARgamma ligands that separate proatherogenic activities from antidiabetic and antiatherogenic activities.
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PMID:Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. 1097 14

CD36 has been associated with diverse normal and pathologic processes. These include scavenger receptor functions (uptake of apoptotic cells and modified lipid), lipid metabolism and fatty acid transport, adhesion, angiogenesis, modulation of inflammation, transforming growth factor-beta activation, atherosclerosis, diabetes and cardiomyopathy. Although CD36 was identified more than 25 years ago, it is only with the advent of recent genetic technology that in-vivo evidence has emerged for its physiologic and pathologic relevance. As these in-vivo studies are expanded, we will gain further insight into the mechanism(s) by which CD36 transmits a cellular signal, and this will allow the design of specific therapeutics that impact on a particular function of CD36.
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PMID:CD36 and atherosclerosis. 1104 91

Both lipoproteins and the endothelium play critical roles in the initiation and progression of atherosclerosis. An understanding of the interactions between lipoproteins and the endothelium facilitates our understanding of atherogenesis and could suggest new therapeutic targets. Lipoproteins have important effects on endothelial cells. Atherogenic lipoproteins such as remnants, low-density lipoprotein (LDL), and oxidized LDL act on endothelial cells to cause upregulation of endothelial adhesion molecules and selectins, promotion of oxygen radicals, increased apoptosis, and reduced endothelium-dependent relaxation. Antiatherogenic lipoproteins such as HDL protect endothelial cells from oxidative stress and apoptosis and reduce adhesion molecule expression. Conversely, the endothelium has major effects on lipoprotein metabolism and function. Several lipases, including lipoprotein lipase, hepatic lipase, endothelial lipase, and secretory phospholipase A2, are bound to the endothelial cell matrix and have the ability to hydrolyze lipoprotein triglycerides and phospholipids. Furthermore, endothelial cells express a variety of lipoprotein receptors including the VLDL receptor, scavenger receptor A, SR-BI, CD36, and LOX-1, although little is known about their function on endothelial cells. Although a great deal is known about endothelial-lipoprotein interactions, more research is needed in this important area.
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PMID:The endothelium and lipoproteins: insights from recent cell biology and animal studies. 1112 8


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