High-density lipoproteins: marker of cardiovascular risk and therapeutic target

The high-density lipoproteins (HDLs) are complex, polymolecular assemblies produced by the jejunum, liver, in serum, and on the surface of macrophages. HDL cholesterol (HDL-C) levels are an independent predictor of risk for cardiovascular events in both men and women. High serum levels of this lipoprotein are associated with reduced risk for atherosclerosis and its clinical sequelae, such as myocardial infarction, ischemic stroke, and death. The molecular basis for the apparent vasculoprotection afforded by elevated HDL-C is widely attributed to the ability of HDL particles to drive reverse cholesterol transport. The proteosome (protein cargo) of HDL also appears to endow this lipoprotein with a capacity to reduce oxidized lipids, promote endothelial cell nitric oxide production, reduce adhesion molecule expression, inhibit platelet activation, stimulate endothelial proliferation and inhibit apoptosis, and reduce inflammatory mediator expression, among other functions. Recent investigation suggests that among patients with coronary artery disease, HDL can also be dysfunctional, yielding a pro-inflammatory and pro-oxidative phenotype. Numerous drugs are currently in development in an effort to devise the means by which to optimally increase serum levels of functional, antiatherogenic HDL species. These drugs exploit a diverse range of mechanisms with potential for beneficially impacting the development and progression of atherosclerotic disease.