Low levels of high-density lipoprotein (HDL) particles were first linked to increased risk of cardiovascular dis-ease(CVD) >40 years ago. Because analytic ultracentrifuga-tion, the method used for those pioneering studies, is complex and time consuming, clinical investigators began to use HDL cholesterol (HDL-C) as a surrogate measure for HDL concentration. Clinical, epidemiological, and genetic studies provide robust evidence that low HDL-C levels associate with clinically significant CVD. Moreover, atherosclerosis increases markedly in hypercholesterolemic mice deficient in apolipo-protein (apoA)-I, the major HDL protein, whereas overex-pression of human apoA-I dramatically retards atherosclerosis in hypercholesterolemic mice. Many lines of evidence indicate that apoA-I and HDL promote cholesterol efflux from macrophages, a key step in atherogenesis. Taken together, these findings provide strong evidence that apoA-I plays a key role in HDL's cardioprotective activities.
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