Antiatherogenic Effects of Small HDL and Therapeutic Roles
Our understanding of the relationship between the atheroprotective activities of HDL and heterogeneity of HDL particles has advanced greatly. HDL particles are highly heterogeneous in structure, intravascular metabolism and antiatherogenic activity. In this review, we discuss new findings on the antiatherogenic properties of HDL particles. Small, dense HDL possesses potent antioxidative activity but this is compromised under conditions of atherogenic dyslipidemia. HDL functional deficiency frequently coincides with reductions in HDL-cholesterol concentration and alterations in HDL metabolism and structure. Formation of small, dense HDL particles with attenuated antiatherogenic activity can be mechanistically related to HDL enrichment in triglycerides and in serum amyloid A, depletion of cholesteryl esters, covalent modification of HDL apolipoproteins and attenuated antiatherogenic function of apolipoprotein AI. Low circulating levels of HDL cholesterol might, therefore, be associated with the defective functionality of small HDL particles of abnormal structure and composition. In common metabolic diseases, such as type 2 diabetes and metabolic syndrome, deficiency of HDL particle number and function favor accelerated atherosclerosis. Therapeutic normalization of the quantity, quality and biological activities of HDL particles thus represents a novel approach to attenuating atherosclerosis in dyslipidemic individuals with metabolic disease. Cholesteryl ester transfer protein inhibitors, nicotinic acid, reconstituted HDL and other HDL-raising agents are being investigated. Induction of selective increase in the circulating concentrations of small, dense HDL3 particles with increased antiatherogenic activity seems especially promising, particularly for therapy of atherogenic dyslipidemia.

Atherogenic dyslipidemia is a major risk factor for premature development of cardiovascular disease. This state represents an imbalance in favor of circulating levels of proatherogenic, cholesterol-rich, apolipoprotein B (apoB)-containing lipoproteins, such as LDL, rather than antiatherogenic apolipoprotein AI (apo AI)-containing HDL. Large, prospective, epidemiological studies reveal that low HDL-cholesterol concentrations constitute an independent predictive risk factor for coronary heart disease (CHD); indeed, CHD risk is elevated by approximately 3% in women and 2% in men for each decrement of 0.0259 mM (1 mg/dl) in HDL-C. The imbalance between circulating levels of atherogenic lipoproteins (LDL, VLDL and intermediate density lipoprotein) relative to those of HDL is associated with induction of endothelial dysfunction, which is in turn intimately related to inflammation and OXIDATIVE STRESS; as a result, dyslipidemia, inflammation and oxidative stress are closely interrelated in the development of atherosclerosis.

Inflammation is a systemic response aimed at decreasing the toxic effects of harmful agents and repairing damaged tissue, and is implicated in a wide range of pathologies. Chronic, low-grade inflammation is a characteristic feature of atherosclerosis, and is typically identified by raised serum levels of C-reactive protein, which is also a major cardiovascular risk factor. Oxidative stress, an integral component of inflammation, involves an imbalance that favors pro-oxidant over antioxidant factors, and typically underlies endothelial dysfunction—a central process in the pathophysiology of atherosclerosis. Endothelial injury and activation involves both excessive penetration and intimal retention of LDL, together with monocyte recruitment and differentiation and activation of macrophages in the arterial wall. As a direct consequence, a local inflammatory response is triggered with excessive production of pro-oxidants, such as reactive oxygen, nitrogen and chlorine species. Indeed, analyses of plaque composition reveal accumulation of products of protein and lipid oxidation consistent with the presence of local oxidative stress. Preferential retention of LDL in the arterial wall via proteoglycan binding makes this lipoprotein a major substrate for oxidation by arterial wall cells, and LDL is seen in increased concentrations at sites of inflammation.

Indeed, oxidized LDL (oxLDL) has multiple proatherogenic properties, which include induction of cholesterol accumulation in macrophages as well as potent proinflammatory, immunogenic, apoptotic and cytotoxic activities. Most of the proinflammatory properties of oxLDL arise from bioactive products of LDL lipid peroxidation. As a result, LDL oxidation further propagates the inflammatory process in the arterial wall, thereby accelerating atherogenesis. Atherosclerosis can be regarded, therefore, as a chronic inflammatory disease of the arterial wall, mediated in part by oxLDL and other proinflammatory agents, such as cytokines, metalloproteases and phospholipases, produced by inflammatory macrophages and macrophage-derived foam cells.

Increasing concentrations of HDL progressively reduce cardiovascular risk and protect against CHD even in the presence of elevated LDL levels. In this review, we discuss new findings on the antiatherogenic properties of HDL particles, including their ability to protect against cellular accumulation of cholesterol, oxidative stress and inflammation in the arterial wall, with a major emphasis on HDL particle heterogeneity. Indeed, new evidence identifies SMALL, DENSE HDL as potent antiatherogenic particles, whose activities are impaired in common metabolic diseases, such as type 2 diabetes mellitus and metabolic syndrome.