Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities.
Oxidative stress, an emerging risk factor for premature atherosclerosis and cardiovascular disease, mediates the formation of proinflammatory, pro-atherogenic oxidized low-density lipoprotein (oxLDL) in the arterial intima. Circulating HDL particles, and particularly small, dense, protein-rich HDL3, may provide potent protection of LDL in vivo from oxidative damage by free radicals in the arterial intima, resulting in the inhibition of the generation of proinflammatory oxidized lipids, primarily lipid hydroperoxides (LOOH) but also short-chain oxidized phospholipids (oxPL). HDL-mediated inactivation of LOOH involves initial transfer of phospholipid hydroperoxides (PLOOH) from LDL to HDL3, which is governed by the rigidity of the surface monolayer of HDL, and subsequent reduction of PLOOH by redox-active Met residues of apolipoprotein A-I (apoA-I) with the formation of phospholipid hydroxides (PLOH) and methionine sulphoxides. HDL-associated enzymes may in turn contribute to the hydrolytic inactivation of short-chain oxPL. Mounting evidence suggests that the integrated antioxidative activity of HDL appear to be defective in atherogenic dyslipidaemias involving low HDL-cholesterol levels; anomalies in the proteome and lipidome of HDL particles in dyslipidaemic patients may underlie such functional deficiency. Pharmacological normalization of HDL metabolism concomitantly with correction of circulating levels, composition and biological activities of HDL particles, with enrichment in apoA-I and reduction in HDL surface rigidity, may constitute an efficacious therapeutic approach to attenuate atherosclerosis in dyslipidaemic patients at high cardiovascular risk.
Kontush
Anatol
A
National Institute for Health and Medical Research (INSERM), Dyslipidemia, Inflammation and Atherosclerosis Research Unit (UMR 939), Paris, France. kontush@chups.jussieu.fr
Chapman
M John
MJ
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D018384:Oxidative Stress
D000975:Antioxidants; D008075:Lipoproteins, HDL