title: PGC-1α ameliorates AngiotensinII-induced eNOS dysfunction in human aortic endothelial cells.
abstract: Increasing evidences support that PGC-1α participates in regulating endothelial homeostasis, in part by mediating endothelial nitric oxide (NO) synthase (eNOS) activity and NO production. However, the molecular mechanisms by which PGC-1α regulates eNOS activity are not completely understood. In the present study, we investigated the effects of PGC-1α on eNOS dysfunction and further explore the underlying mechanisms. The results showed that PGC-1α expression was downregulated after AngiotensinII (AngII) treatment and paralleled with the decreased NO generation in human aortic endothelial cells. Overexpression of PGC-1α with adenovirus or pharmacological agonist ameliorated AngII-induced the decrease of NO generation, evidenced by the restoration of cGMP and nitrite concentration. Rather than affecting eNOS expression and uncoupling, PGC-1α inhibited AngII-induced decrease of eNOS serine 1177 phosphorylation through activation of PI3K/Akt signaling. In addition, PGC-1α overexpression suppressed AngII-induced the increase of PP2A-A/eNOS interaction and PP2A phosphatase activity, with a concomitant decrease in PP2A phosphorylation, leading to eNOS serine 1177 phosphorylation. However, pharmacological inhibition of PI3K/Akt signaling blunted the observed effect of PGC-1α on PP2A activity. Taken together, our findings suggest that PGC-1α overexpression improves AngII-induced eNOS dysfunction and that improved eNOS dysfunction is associated with activated PI3K/Akt pathway, impaired PP2A activity and reduced PP2A-A/eNOS association. These date indicate that forced PGC-1α expression may be a novel therapeutic approach for endothelial dysfunction.
authors.affiliation: Department of Anesthesiology, Second Affiliated Hospital of Guangzhou, University of TCM, Guangzhou 510120, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cardiology, The Third Hospital of Hebei Medical University, Hebei 050051, China. Electronic address: hbsjzgxy@icloud.com.
authors.forename: Xiao-Yong
authors.initials: XY
authors.lastname: Geng
authors.affiliation: Department of Cardiology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China. Electronic address: congxl_cardio@163.com.
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Cong
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine; D014162:Transfection; D015854:Up-Regulation
chemical_list: D009573:Nitrites; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D000804:Angiotensin II; D009569:Nitric Oxide; D012694:Serine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2; D006152:Cyclic GMP
keywords: Endothelial dysfunction; PGC-1α; PI3K/Akt; PP2A; eNOS