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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Traditional risk factors for atherosclerosis are well known and their control decreases importantly the appearance of the disease. These factors are the genetic charge, dyslipidemia, smoking, systemic arterial hypertension, diabetes, obesity, gender, age, stress, estrogen levels in women, and life style. However, in the last decade, new risk factors have been identified especially for coronary and cerebrovascular atherosclerosis. Among these factors, the inflammatory process has been pointed out in which acute stage reactants participate, such as C-reactive protein, leukocyte count, globular sedimentation, multiple cytokines, alpha tumor necrosis factor, vascular and cellular adhesion molecules, some metalloproteinases, pregnancy-associated plasma protein A, lipoprotein-associated phospholipase A2, angiotensin II, and very probably infection. This article discusses the mechanism by which these markers participate in the atherosclerotic process and their value as predictors of future coronary events, as well as to what extent current therapeutics can contribute to decrease these events and to improve patient care.
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PMID:[Inflammation in atherosclerosis]. 1296 66

LDL (low-density lipoprotein) is the major carrier of cholesterol in human plasma, and as such is intimately involved in the process of atherosclerosis. The lipoprotein class comprises a number of distinct subfractions, and is commonly divided into large, intermediate and small sized particles. Small, dense LDLs are held to be particularly atherogenic, since these particles are retained preferentially by the artery wall, are readily oxidized and carry an enzyme believed to have an important role in atherosclerosis, i.e. lipoprotein-associated phospholipase A(2). Generation of small, dense LDL occurs by intravascular lipoprotein remodelling as a result of disturbances such as Type II diabetes, metabolic syndrome, renal disease and pre-eclampsia. The key predisposing factor is the development of hypertriglyceridaemia, in particular elevation in the plasma concentration of large, triacylglycerol-rich VLDL (very-low-density lipoprotein). This leads to the formation of slowly metabolized LDL particles (5-day residence time), which are subject to exchange processes that remove cholesteryl ester from the particle core and replace it with triacylglycerol. LDL, so altered, is a potential substrate for hepatic lipase; if the activity of the enzyme is high enough, lipolysis will generate smaller, denser particles. Correction of the dyslipidaemia associated with small, dense LDL is possible using fibrates and statins, and this may contribute to the clinical benefits seen with these drugs. Fibrates act to lower plasma triacylglycerol (VLDL) levels, and so correct the underlying metabolic disturbance. Statins remove VLDL particles via receptor-mediated pathways and reduce the residence time (and hence limit the potential for remodelling) of LDL in the circulation.
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PMID:Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein. 1450 81

Inflammatory reactions contribute to the pathogenesis of cardiovascular conditions such as atherosclerosis and ischemic damage in acute myocardial infarction (AMI). Among the mediators involved in inflammation are secretory phospholipase A2 group II (sPLA2-II) enzymes. Though some cells constitutively express sPLA2-II, the synthesis by cells such as hepatocytes is typical for an acute-phase reactant. Recent literature suggests multiple roles for sPLA2-II in cardiovascular disease. In this review we discuss the role of sPLA2-II in various in vivo and in vitro models of atherosclerosis or AMI, including the therapeutic perspective of sPLA2-II inhibitors. It was concluded that sPLA2-II appears to be an important inflammatory mediator of cardiovascular disease.
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PMID:Type II secretory phospholipase A2 in cardiovascular disease: a mediator in atherosclerosis and ischemic damage to cardiomyocytes? 1452 8

Death of macrophages and smooth muscle cells (SMC) can lead to progression of atherosclerosis. Mildly oxidised low-density lipoprotein (mildly-oxLDL) induced more overall death and apoptosis than moderately oxidised LDL, in human monocyte-macrophages (HMM). Mildly-oxLDL also induced more overall death in human SMC than did moderately-oxLDL. Mildly-oxLDL contained more hydroperoxides, but less oxysterol, malondialdehyde and negative charge than moderately-oxLDL. Specific inhibition of lipoprotein-associated phospholipase A(2) (by SB222657) diminished death induction in HMM by both oxLDL types. Peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist (GW9662) and agonist (ciglitazone) experiments suggested that non-hydrolysed, oxidised phospholipids in oxLDL activate PPARgamma as a cellular defence mechanism. These results may be relevant to LDL oxidation within atherosclerotic plaques and may suggest strategies for combating atherosclerosis progression.
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PMID:Mildly oxidised LDL induces more macrophage death than moderately oxidised LDL: roles of peroxidation, lipoprotein-associated phospholipase A2 and PPARgamma. 1455 May 63

The quantitative or qualitative decline of high-density lipoprotein (HDL) is linked to the pathogenesis of atherosclerosis because of its antiatherogenic functions, including the mediation of reverse cholesterol transport from the peripheral cells to the liver. We have recently shown that group X secretory phospholipase A(2) (sPLA(2)-X) is involved in the pathogenesis of atherosclerosis via potent lipolysis of low-density lipoprotein (LDL) leading to macrophage foam cell formation. We demonstrate here that sPLA(2)-X as well as group V secretory PLA(2) (sPLA(2)-V), another group of sPLA(2) that can potently hydrolyze phosphatidylcholine (PC), also possess potent hydrolytic potency for PC in HDL linked to the production of a large amount of unsaturated fatty acids and lysophosphatidylcholine (lysoPC). In contrast, the classical types of group IB and IIA secretory PLA(2)s evoked little, if any, lypolytic modification of HDL. Treatment with sPLA(2)-X or -V also caused an increase in the negative charge of HDL with no oxidation and little modification of apolipoprotein AI (apoAI). Modification with sPLA(2)-X or -V resulted in significant decrease in the capacity of HDL to cause cellular cholesterol efflux from lipid-loaded macrophages. Immunohistochemical analysis revealed significant expression of sPLA(2)-X in foam cell lesions in the arterial intima of Watanabe heritable hyperlipidemic (WHHL) rabbit. These findings suggest that lipolytic modification of HDL by sPLA(2)-X or -V causes drastic change of HDL in terms of the production of a large amount of unsaturated fatty acids and lysoPC linked to the reduction of its antiatherogenic functions. These sPLA(2)-mediated modifications of plasma lipoproteins might be relevant to the pathogenesis of atherosclerosis.
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PMID:Group V and X secretory phospholipase A(2)s-induced modification of high-density lipoprotein linked to the reduction of its antiatherogenic functions. 1457 96

The formation of foam cells, a critical event in the early stages of atherosclerosis, is associated with the uptake of oxidized low-density lipoprotein (oxLDL) by macrophages and the subsequent accumulation of cholesterol ester formed by the catalytic action of acyl-CoA: cholesterol acyltransferase (ACAT). Although free cholesterol, a substrate for ACAT, is supplied from the intracellular cholesterol pool, little is known about the pathways involved in the supply of fatty acids, precursors for fatty acyl-CoA as another substrate for ACAT. Our recent studies were undertaken to examine the possible involvement of phospholipase A2 (PLA2) in the supply of fatty acids required for the cholesterol esterification. In mouse peritoneal macrophages and RAW264.7 macrophages, oxLDL induced the liberation of fatty acids from membrane phospholipids to increase cholesterol ester having the fatty acids as an acyl chain. The changes in these lipids were suppressed by the inhibition of cytosolic PLA2 (cPLA2). Although oxLDL did not affect the activity or amounts of cPLA2, preincubation with oxLDL enhanced the release of fatty acids induced by Ca2+ ionophore, which accelerates the hydrolytic action of cPLA2. We further observed that oxLDL induced the generation of ceramide through the de novo synthesis. Exogenous ceramide and 13-hydroxyoctadecadienoic acid, an oxidized lipid in oxLDL particles, also stimulated fatty acid release. Based on these findings, we propose that oxLDL activates cPLA2 to supply fatty acids required for the cholesterol esterification, through the acceleration of the hydrolytic action of cPLA2 by endogenous ceramide and by oxidized lipids in oxLDL particles in macrophages.
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PMID:[Involvement of phospholipase A2 in the supply of fatty acids required for cholesterol esterification associated with uptake of oxidized low-density lipoprotein in macrophages]. 1457 30

SB-480848 is a reversible lipoprotein-associated phospholipase A2 inhibitor under development by GlaxoSmithKline for the potential treatment of atherosclerosis. Phase II trials with SB-480848 are currently underway.
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PMID:SB-480848. GlaxoSmithKline. 1508 4

Members of the serum paraoxonase (PON) family have been identified in mammals and other vertebrates, and in invertebrates. PONs exhibit a wide range of physiologically important hydrolytic activities, including drug metabolism and detoxification of nerve agents. PON1 and PON3 reside on high-density lipoprotein (HDL, 'good cholesterol') and are involved in the prevention of atherosclerosis. We describe the first crystal structure of a PON family member, a variant of PON1 obtained by directed evolution, at a resolution of 2.2 A. PON1 is a six-bladed beta-propeller with a unique active site lid that is also involved in HDL binding. The three-dimensional structure and directed evolution studies permit a detailed description of PON1's active site and catalytic mechanism, which are reminiscent of secreted phospholipase A2, and of the routes by which PON family members diverged toward different substrate and reaction selectivities.
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PMID:Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. 1509 21

Type VII phospholipase A2 associated to low density lipoproteins (LDL), also known as platelet-activating factor acetylhydrolase, has been recently indicated as a new non traditional and independent risk factor of coronary disease. After the classification of phospholipase A2 family enzymes, a review is made of the recent physiologic and biochemical knowledges on A2 type VII phospholipase LDL lipoproteins-associated and the role developed in lipoproteins metabolism and atherogenesis. Finally, future therapeutic implications and perspectives depending on these knowledges are pointed out especially by using molecules inhibiting the activity of the enzyme in atherosclerosis therapy. The evaluation of circulating activity of the enzyme may be useful in the prevention and recognition of acute coronary syndromes.
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PMID:[Lipoprotein-associated phospholipase A2: importance and perspectives]. 1527 48

The long-term success of cardiac allograft transplantation is limited by the development of a particular type of coronary atherosclerosis referred to as transplant vascular disease (TVD). Although the exact pathogenesis of TVD remains to be established, there is growing evidence that TVD involves immunological mechanisms operating in a milieu of nonimmunological risk factors. These immunological events constitute the principal initiating stimuli, resulting in endothelial injury with consequent myointimal hyperplasia, extracellular matrix synthesis and invocation of proteoglycan (PG)-lipoprotein interactions, leading, ultimately, to lipid retention in the vessel wall. The profound early 'insudation' of apolipoproteins along with uncertain endothelial 'intactness' in human coronary arteries in the transplanted heart, suggest that permeability of these vessel walls must be altered. Further, frequent and typically diffuse intracellular and extracellular accumulation of lipids and PGs in both the intimal and medial layers of cardiac allograft arteries has affirmed that the alloimmune environment accompanied with aberrant expression of extracellular matrix components, especially PGs, may strongly promote lipid imbibition in the allograft vascular bed, leading to TVD. In summary, the cumulative data support the view that profound lipid accumulation occurs in allograft arteries beginning very early post-transplantation, contributing to intimal thickening; that lipoproteins enter and are trapped in the subendothelial tissue, apparently through interactions with PGs; that with direct glycosaminoglycans, apolipoprotein interactions may occur, or they may occur through bridging molecules like phospholipase A2 and lipoprotein lipase; and that prolonged residence in the intima leads to lipoprotein modification, with subsequent modulation of biological processes that promote atherogenesis.
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PMID:Transplant vascular disease: role of lipids and proteoglycans. 1583 69


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