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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1125.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Stimulation of Cell Surface F₁-ATPase Activity by Apolipoprotein A-I Inhibits Endothelial Cell Apoptosis and Promotes Proliferation

Claudia Radojkovic; Annelise Genoux; Véronique Pons; Guillaume Combes; Hugo de Jonge; Eric Champagne; Corinne Rolland; Bertrand Perret; Xavier Collet; François Tercé; Laurent O. Martinez

From the INSERM U563 (C.R., A.G., V.P., G.C., E.C., C.R., B.P., X.C., F.T., L.O.M.), Département Lipoprotéines et Médiateurs Lipidiques, Toulouse, France; Université de Toulouse (C.R., A.G., V.P., G.C., E.C., C.R., B.P., X.C., F.T., L.O.M.), UPS, IFR150, IFR-BMT, Toulouse, France; the Departamento de Bioquímica Clínica e Inmunología (C.R.), Facultad de Farmacia, Universidad de Concepción, Concepción, Chile; Growth Factors Group (H.d.J.), MRC Centre, Cambridge, UK; the Division of Endocrinology and Metabolism, Department of Biology, Faculty of Science (H.d.J.), Utrecht University, The Netherlands.

Correspondence to Laurent O. Martinez, INSERM U563, Bât. C, Hôpital Purpan, BP 3048, 31024 Toulouse cedex 03, France. E-mail Laurent.Martinez{at}inserm.fr

Objectives— Several findings argue for a protective effect of high-density lipoproteins (HDLs) against endothelial dysfunction. The molecular mechanisms underlying this protective effect are not fully understood, although recent works suggest that the actions of HDL on the endothelium are initiated by multiple interactions between HDLs (lipid or protein moiety) and cell surface receptors. We previously showed that the mitochondrial related F₁-ATPase is a cell surface receptor for HDLs and their main atheroprotective apolipoprotein (apoA-I). Herein we test the hypothesis that the cell surface F₁-ATPase may contribute to the ability of apoA-I and HDLs to maintain endothelial cell survival.

Methods and Results— Cell imaging and binding assays confirmed the presence of the F₁-ATPase at the surface of human umbilical vein endothelial cells (HUVECs) and its ability to bind apoA-I. Cell surface F₁-ATPase activity (ATP hydrolysis into ADP) was stimulated by apoA-I and was inhibited by its specific inhibitor IF₁-H49K. Furthermore the antiapoptotic and proliferative effects of apoA-I on HUVECs were totally blocked by the F₁-ATPase ligands IF₁-H49K, angiostatin and anti-βF₁-ATPase antibody, independently of the scavenger receptor SR-BI and ABCA1.

Conclusion— This study suggests an important contribution of cell surface F₁-ATPase to apoA-I-mediated endothelial cell survival, which may contribute to the atheroprotective functions of apoA-I.

This work proposes a new role for the cell surface F₁-ATPase/apoA-I tandem in endothelial cell protection. F₁-ATPase activation by apoA-I or inhibition by its inhibitor IF₁-H49K drives endothelial cells toward proliferation or apoptosis, respectively. Therefore, F₁-ATPase pathway contributes to endothelial cell survival responses to apoA-I, possibly through extracellular production of ADP.

Key Words: ATP synthase • apolipoprotein A-I • vascular endothelial cells • apoptosis