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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1843.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Preferential Sphingosine-1-Phosphate Enrichment and Sphingomyelin Depletion Are Key Features of Small Dense HDL3 Particles

Relevance to Antiapoptotic and Antioxidative Activities

Anatol Kontush; Patrice Therond; Amal Zerrad; Martine Couturier; Anne Négre-Salvayre; Juliana A. de Souza; Sandrine Chantepie; M. John Chapman

From the Université Pierre et Marie Curie-Paris 6 (A.K., J.A.d.S., S.C., M.J.C.), Paris; AP-HP, Groupe hospitalier Pitié-Salpétrière (A.K., J.A.d.S., S.C., M.J.C.), Paris; INSERM, Dyslipoproteinemia and Atherosclerosis Research Unit 551 (A.K., P.T., A.Z., M.C., A.N.-S., J.A.d.S., S.C., M.J.C.), Paris; Université Paris Descartes, Department of Biochemistry (P.T., A.Z., M.C.), EA 3617, Paris; and INSERM Unit 466 (A.N.-S.), CHU Rangueil, Toulouse, France.

Correspondence to Dr Anatol Kontush, INSERM Unité 551, Pavillon Benjamin Delessert, Hôpital de la Pitié, 83 boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail kontush{at}chups.jussieu.fr

Objective— The purpose of this study was to define heterogeneity in the molecular profile of lipids, including sphingomyelin and sphingosine-1-phosphate, among physicochemically-defined HDL subpopulations and potential relevance to antiatherogenic biological activities of dense HDL3.

Methods and Results— The molecular profile of lipids (cholesteryl esters, phospholipids, sphingomyelin, and sphingosine-1-phosphate) in physicochemically-defined normolipidemic HDL subpopulations was determined by high-performance liquid chromatography and gas chromatography. As HDL particle size and molecular weight decreased with increment in density, molar lipid content diminished concomitantly. On a % basis, sphingomyelin abundance diminished in parallel with progressive increase in HDL density from HDL2b (12.8%) to HDL3c (6.2%; P<0.001); in contrast, sphingosine-1-phosphate was preferentially enriched in small HDL3 (40 to 50 mmol/mol HDL) versus large HDL2 (15 to 20 mmol/mol HDL; P<0.01). Small HDL3c was equally enriched in LpA-I particles relative to LpA-I:A-II. The sphingosine-1-phosphate/sphingomyelin ratio correlated positively with the capacities of HDL subspecies to attenuate apoptosis in endothelial cells (r=0.73, P<0.001) and to retard LDL oxidation (r=0.58, P<0.01).

Conclusions— An elevated sphingosine-1-phosphate/sphingomyelin ratio is an integral feature of small dense HDL3, reflecting enrichment in sphingosine-1-phosphate, a key antiapoptotic molecule, and depletion of sphingomyelin, a structural lipid with negative impact on surface fluidity and LCAT activity. These findings further distinguish the structure and antiatherogenic activities of small, dense HDL.

Preferential sphingosine-1-phosphate enrichment, but sphingomyelin depletion, distinguish normolipidemic small, dense HDL3 from large HDL2. Elevated sphingosine-1-phosphate/sphingomyelin ratio constitutes a hallmark of the lipid moiety of small dense HDL3 particles and is implicated in their antiatherogenic activity.

Key Words: sphingolipids • phospholipid molecular species • cholesteryl esters • HDL particle remodeling

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