PURPOSE OF REVIEW: Despite the best efforts in reduction of low-density lipoprotein cholesterol, most cardiovascular events are not being prevented. Because high-density lipoprotein (HDL) promotes reverse cholesterol transport and other antiatherogenic effects, interventions aimed at raising HDL cholesterol or mimicking its beneficial effects may greatly improve treatment and prevention of cardiovascular disease. This article reviews the antiatherogenic effects of HDL, recent insights into the mechanisms of action of currently available, and emerging HDL-based therapies. RECENT FINDINGS: New insights into the basic science of HDL function and metabolism (such as the discovery of beta-chain ATP synthase as a hepatic catabolic HDL receptor) are further characterizing the importance of HDL in atheroprotection and identifying novel targets of drug development. Nicotinic acid, fibrates, statins, and thiazolidinediones not only increase HDL cholesterol but also alter HDL subpopulation size and composition. Furthermore, these drugs promote direct antiatherogenic effects of HDL (antioxidation, anti-inflammation, antithrombotic effects, endothelial stabilization). Emerging HDL-raising therapies (such as cholesteryl ester transfer protein inhibitors and 1,2-dimyristoyl-sn-glycero-phosphocholine) and novel interventions that mimic HDL's beneficial effects (such as apolipoprotein AImilano and apolipoprotein AI mimetic peptides) are proving beneficial in animal and human studies. SUMMARY: An understanding of the atheroprotective mechanisms of HDL is essential for the rational use of currently available drugs and directed development of new drugs. Increasing total HDL cholesterol may not be as important as increasing the functional properties of HDL. Cardiovascular disease treatment and prevention can be improved by combining current low-density lipoprotein-based strategies with effective HDL-based interventions.
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