HDL Cholesterol and Protective Factors in Atherosclerosis

Abstract

Abstract-A low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for cardiovascular disease. Epidemiological and clinical studies provide evidence that HDL-C levels are linked to rates of coronary events. The cardioprotective effects of HDL-C have been attributed to its role in reverse cholesterol transport, its effects on endothelial cells, and its antioxidant activity. Although some clinical trials suggest a benefit of raising HDL-C to reduce risk, further studies are needed, and HDL-C is still not considered a primary target of therapy in the National Cholesterol Education Program guidelines. However, HDL-C should be considered as part of the patient's overall profile of established risk factors in determining treatment strategies. T he association between low levels of high-density lipoprotein cholesterol (HDL-C) and an increased risk for cardiovascular disease has been well established through epidemiological and clinical studies. 1 This relationship is supported by the potential antiatherogenic properties of HDL, including its mediation of reverse cholesterol transport, in which cholesterol from peripheral tissues is returned to the liver for excretion in the bile. 2 This review considers the potential mechanisms by which HDL-C may exert its antiatherogenic effects, discusses disorders of HDL and how to interpret them in the clinical setting, and presents current and potential treatment strategies for patients with low HDL-C. Structure and Metabolism of HDL and Relation to Potential Mechanisms of BenefitOverview of HDL Structure and Heterogeneity HDL is a class of heterogeneous lipoproteins containing approximately equal amounts of lipid and protein. 1 HDL particles are characterized by high density (Ͼ1.063 g/mL) and small size (Stoke's diameter ϭ5 to 17 nm). The various HDL subclasses vary in quantitative and qualitative content of lipids, apolipoproteins, enzymes, and lipid transfer proteins, resulting in differences in shape, density, size, charge, and antigenicity. Most of apolipoprotein A-I (apo A-I), the predominant HDL protein, migrates in agarose gels with ␣-electrophoretic mobility and is designated ␣-LpA-I. This fraction accounts for almost all of the cholesterol quantified in the clinical laboratory as HDL-C. ␣-HDL can be further fractionated by density into HDL 2 and HDL 3 , by size, or by apolipoprotein composition. Approximately 5% to 15% of apo A-I in human plasma is associated with particles with pre-␤-electrophoretic mobility. These can be further differentiated into pre-␤ 1 -LpA-I, pre-␤ 2 -LpA-I, and pre-␤ 3 -LpA-I particles. These lipid-poor particles are increased in extravascular compartments where reverse cholesterol transport takes place. 3 The origin of HDL particles with pre-␤-electrophoretic mobility is not entirely clear. Several mechanisms have been proposed, including direct secretion into plasma from hepatocytes or enterocytes; release during the interconversion of various HDL subpopulations by phospholipid transfer protein (PLTP), cholesteryl ...

Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells

“…H igh levels of low-density lipoprotein (LDL) 4 and low levels of high-density lipoprotein (HDL) are thought to increase the risk of atherosclerosis and its associated cardiovascular disease (1,2). Thus, an imbalance in the concentrations of plasma LDL and HDL is a critical biomarker for atherosclerosis.…”

“…In some cases of these diseases, abnormal or proinflammatory HDL is accumulated (7). Reverse cholesterol transport is known to be an important mechanism allowing HDL to prevent the accumulation of cholesterol in leukocytes and the formation of foam cells in the intima of vessel walls (1,2). Recent studies, however, have suggested that HDL exerts a variety of anti-atherogenic or anti-inflammatory actions independent of changes in cholesterol metabolism (1,8).…”

“…Reverse cholesterol transport is known to be an important mechanism allowing HDL to prevent the accumulation of cholesterol in leukocytes and the formation of foam cells in the intima of vessel walls (1,2). Recent studies, however, have suggested that HDL exerts a variety of anti-atherogenic or anti-inflammatory actions independent of changes in cholesterol metabolism (1,8). Leukocyte adhesion to endothelial cells and subsequent transmigration into the subendothelial space or outside the vascular system are commonly observed at early stages of inflammatory diseases and are thought to be critical in their initiation and progression (1,8,9).…”

“…Recent studies, however, have suggested that HDL exerts a variety of anti-atherogenic or anti-inflammatory actions independent of changes in cholesterol metabolism (1,8). Leukocyte adhesion to endothelial cells and subsequent transmigration into the subendothelial space or outside the vascular system are commonly observed at early stages of inflammatory diseases and are thought to be critical in their initiation and progression (1,8,9). HDL has been shown to induce the inhibition of the adhesion of leukocytes to endothelial cells and their transmigration, the inhibition of proinflammatory gene expression in endothelial cells, and the activation of endothelial NO synthase (eNOS) (1,8,10).…”

“…Leukocyte adhesion to endothelial cells and subsequent transmigration into the subendothelial space or outside the vascular system are commonly observed at early stages of inflammatory diseases and are thought to be critical in their initiation and progression (1,8,9). HDL has been shown to induce the inhibition of the adhesion of leukocytes to endothelial cells and their transmigration, the inhibition of proinflammatory gene expression in endothelial cells, and the activation of endothelial NO synthase (eNOS) (1,8,10). Furthermore, HDL protects normal endothelial cell functions by inhibiting apoptosis and stimulating re-endothelialization after injury (10).…”