on April 16, 2009
Published online before print April 16, 2009, doi: 10.1161/ATVBAHA.109.187997
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Submitted on January 29, 2009
Accepted on April 7, 2009
Stimulation of Cell Surface F1-ATPase Activity by Apolipoprotein A-I Inhibits Endothelial Cell Apoptosis and Promotes Proliferation
Claudia Radojkovic ;
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.
* To whom correspondence should be addressed. 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-
F1-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.
Key words: ATP synthase • apolipoprotein A-I • vascular endothelial cells • apoptosis