Emerging therapeutic strategies to enhance HDL function

Abstract

Epidemiologic studies indicate a strong inverse correlation between plasma levels of high-density lipoproteins (HDL) and cardiovascular disease (CVD). The most relevant cardioprotective mechanism mediated by HDL is thought to be reverse cholesterol transport (RCT). New insights in HDL biology and RCT have allowed the development of promising agents aimed to increase HDL function and promote atherosclerosis regression. In this regard, apo-AI analogs and CETP inhibitors dalcetrapib and anacetrapib have aroused a great interest and opened new expectations in the treatment of CVD.

Figure 1

Simplified scheme of reverse cholesterol transport. In the onset and progression of atherosclerotic lesions the uptake of modified LDL (mainly oxidized LDL or oxLDL) by macrophages through a process mediated by scavenger receptors (i.e. SR-A and CD36) that lead to the formation of lipid-loaded cells is critical. This seems to be a reversible process, as HDL-mediated RCT can clear cholesterol from vascular tissues contributing to atherosclerosis regression. HDL acquires cholesterol through a mechanism that involves the receptor SR-BI and transports this cholesterol back to the liver. However, HDL also exchanges lipids with LDL, a process mediated by the CETP that increases LDL cholesterol cargo and potentially enhances their atherogenicity.

Figure 2

Chemical structure of torcetrapib, dalcetrapib and anacetrapib.