Oxidative modification of HDL by lipid aldehydes impacts HDL function.

Reduced levels of high-density lipoprotein (HDL) cholesterol correlate with increased risk for atherosclerotic cardiovascular diseases and HDL performs functions including reverse cholesterol transport, inhibition of lipid peroxidation, and suppression of inflammation, that would appear critical for cardioprotection. However, several large clinical trials utilizing pharmacologic interventions that elevated HDL cholesterol levels failed to provide cardioprotection to at-risk individuals. The reasons for these unexpected results have only recently begun to be elucidated. HDL cholesterol levels and HDL function can be significantly discordant, so that elevating HDL cholesterol levels may not necessarily lead to increased functional capacity, particularly under conditions that cause HDL to become oxidatively modified, resulting in HDL dysfunction. Here we review evidence that oxidative modifications of HDL, including by reactive lipid aldehydes generated by lipid peroxidation, reduce HDL functionality and that dicarbonyl scavengers that protect HDL against lipid aldehyde modification are beneficial in pre-clinical models of atherosclerotic cardiovascular disease.