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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:2169.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

HDL3-Mediated Inactivation of LDL-Associated Phospholipid Hydroperoxides Is Determined by the Redox Status of Apolipoprotein A-I and HDL Particle Surface Lipid Rigidity

Relevance to Inflammation and Atherogenesis

Amal Zerrad-Saadi; Patrice Therond; Sandrine Chantepie; Martine Couturier; Kerry-Anne Rye; M. John Chapman; Anatol Kontush

From the Dyslipidemia and Atherosclerosis Research Unit (UMRS 939) (A.Z.-S., S.C., M.C., M.J.C., A.K.), National Institute for Health and Medical Research (INSERM), Hôpital de la Pitié; UPMC Paris 6 (A.Z.-S., S.C., M.C., M.J.C., A.K.); and the Department of Biochemistry (A.Z.-S., P.T., M.C.), University Paris Descartes, France; and the Heart Research Institute (K.-A.R.), Sydney, Australia.

Correspondence to Dr Anatol Kontush, INSERM U939, Pavillon Benjamin Delessert, Hôpital de la Pitié, 83 boulevard de l'Hôpital, 75651 Paris Cedex 13, France. E-mail kontush{at}chups.jussieu.fr

Objectives— Small dense HDL3 particles of defined lipidome and proteome potently protect atherogenic LDL against free radical-induced oxidation; the molecular determinants of such antioxidative activity in these atheroprotective, antiinflammatory particles remain indeterminate.

Methods and Results— Formation of redox-active phosphatidylcholine hydroperoxides (PCOOH) and redox-inactive phosphatidylcholine hydroxides (PCOH) was initiated in LDL by free radical-induced oxidation. Human HDL3 inactivated LDL-derived PCOOH (–62%, P<0.01) and enhanced accumulation of PCOH (2.1-fold, P<0.05); in parallel, HDL3 accumulated minor amounts of PCOOH. Enzyme-deficient reconstituted dense HDL potently inactivated PCOOH (–43%, P<0.01). HDL3-mediated reduction of PCOOH to PCOH occurred concomitantly with oxidation of methionine residues in HDL3-apolipoprotein AI (apoAI). Preoxidation of methionine residues by chloramine T markedly attenuated PCOOH inactivation (–35%); by contrast, inhibition of HDL3-associated enzymes was without effect. PCOOH transfer rates from oxidized LDL to phospholipid liposomes progressively decreased with increment in the rigidity of the phospholipid monolayer.

Conclusions— The redox status of apoAI and surface lipid rigidity represent major determinants of the potent HDL3-mediated protection of LDL against free radical-induced oxidation. Initial transfer of PCOOH to HDL3 is modulated by the surface rigidity of HDL3 particles with subsequent reduction of PCOOH to PCOH by methionine residues of apoAI.

Redox status of apoAI and surface lipid rigidity of dense HDL3 particles are critical to their potent capacity to protect LDL against free radical-induced oxidation. Transfer of LDL-associated phospholipid hydroperoxides to HDL3 with their subsequent reduction to hydroxides by methionine residues of apoAI is central to such antioxidative activity.

Key Words: small dense HDL • surface rigidity • methionine residues • reduction • apolipoprotein AI • lipid hydroperoxides