Audrey Castaing-Berthou1,2, Nicole Malet1,2, Claudia Radojkovic3, Cendrine Cabou1,2, Stéphanie Gayral1,2, Laurent Olivier Martinez1,2, Muriel Laffargue1,2. 1. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France. 2. University of Toulouse, UMR1048, Paul Sabatier University, Toulouse, France. 3. Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.
Abstract
BACKGROUND/AIMS: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F1-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival. In this study we aimed to further investigate the signaling pathway involved downstream of apoA-I-induced ecto-F1-ATPase activation. METHODS: In human umbilical vein endothelial cells (HUVECs), pharmacological and gene silencing approaches were used to study pathways involved downstream ecto-F1-ATPase activation by apoA-I. RESULTS: ApoA-I and HDL both induced Akt phosphorylation. F1-ATPase inhibitors such as inhibitory factor 1 and oligomycin completely blocked apoA-I-induced Akt phosphorylaton and significantly blocked HDL-induced phosphorylation, indicating that this signaling pathway is dependent on ecto-F1-ATPase activation by apoA-I. Further, we were able to specify roles for the P2Y1-ADPreceptor and the PI3Kβ isoform in this pathway since pharmacological inhibition and silencing of these proteins dramatically inhibited apoA-I-induced Akt phosphorylation and cell proliferation. CONCLUSION: Altogether, these data highlight a key role of the P2Y1/PI3Kβ axis in endothelial cell proliferation downstream of ecto-F1-ATPase activation by apoA-I. Pharmacological targeting of this pathway could represent a promising approach to enhance vascular endothelial protection.
BACKGROUND/AIMS: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F1-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival. In this study we aimed to further investigate the signaling pathway involved downstream of apoA-I-induced ecto-F1-ATPase activation. METHODS: In human umbilical vein endothelial cells (HUVECs), pharmacological and gene silencing approaches were used to study pathways involved downstream ecto-F1-ATPase activation by apoA-I. RESULTS:ApoA-I and HDL both induced Akt phosphorylation. F1-ATPase inhibitors such as inhibitory factor 1 and oligomycin completely blocked apoA-I-induced Akt phosphorylaton and significantly blocked HDL-induced phosphorylation, indicating that this signaling pathway is dependent on ecto-F1-ATPase activation by apoA-I. Further, we were able to specify roles for the P2Y1-ADPreceptor and the PI3Kβ isoform in this pathway since pharmacological inhibition and silencing of these proteins dramatically inhibited apoA-I-induced Akt phosphorylation and cell proliferation. CONCLUSION: Altogether, these data highlight a key role of the P2Y1/PI3Kβ axis in endothelial cell proliferation downstream of ecto-F1-ATPase activation by apoA-I. Pharmacological targeting of this pathway could represent a promising approach to enhance vascular endothelial protection.
Authors: Ilona Kareinen; Marc Baumann; Su Duy Nguyen; Katariina Maaninka; Andrey Anisimov; Minoru Tozuka; Matti Jauhiainen; Miriam Lee-Rueckert; Petri T Kovanen Journal: J Lipid Res Date: 2018-03-26 Impact factor: 5.922
Authors: Jude Gibson; Tom C Russ; Toni-Kim Clarke; David M Howard; Robert F Hillary; Kathryn L Evans; Rosie M Walker; Mairead L Bermingham; Stewart W Morris; Archie Campbell; Caroline Hayward; Alison D Murray; David J Porteous; Steve Horvath; Ake T Lu; Andrew M McIntosh; Heather C Whalley; Riccardo E Marioni Journal: PLoS Genet Date: 2019-11-18 Impact factor: 5.917