title: PGC-1α overexpression suppresses blood pressure elevation in DOCA-salt hypertensive mice.
abstract: Increasing evidences have accumulated that endothelial dysfunction is involved in the pathogenesis of hypertension. Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) has been identified as an essential factor that protects against endothelial dysfunction in vascular pathologies. However, the functional role of PGC-1α in hypertension is not well understood. Using an adenovirus infection model, we tested the hypothesis that PGC-1α overexpression retards the progression of hypertension in deoxycorticosterone acetate (DOCA)-salt mice model through preservation of the function of endothelium. We first demonstrated that PGC-1α expression not only in conductance and resistance arteries but also in endothelial cells was decreased after DOCA-salt treatment. In PGC-1α adenovirus-infected mice, the elevation of blood pressure in DOCA-salt mice was attenuated, as determined using tail-cuff measurement. Furthermore, PGC-1α overexpression inhibited the decrease in nitric oxide (NO) generation and the increase in superoxide anion (O2 (-)) production in DOCA-salt-treated mice, in parallel with improved endothelium-dependent relaxation. Rather than affecting endothelial NO synthase (eNOS) total expression and phosphorylation, PGC-1α significantly inhibited eNOS uncoupling, as evidenced by increased eNOS homodimerization, BH4 levels, GTP-cyclohydrolase 1 (GTPCH1) and dihydrofolate reductase (DHFR) expression and heat-shock protein (Hsp)90-eNOS interaction. Our findings demonstrate that PGC-1α overexpression preserves eNOS coupling, enhances NO generation, improves endothelium-dependent relaxation and thus lowers blood pressure, suggesting that up-regulation of PGC-1α may be a novel strategy to prevent and treat hypertension.
authors.affiliation: Department of Geratology, the First Affiliated Hospital of Xi' an Jiaotong University, Xi'an, 710061 Shannxi, China zhaoqingbin05@126.com.
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, Chencang Hospital, Baoji, 721300 Shannxi, China.
authors.forename: Junfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Geratology, the First Affiliated Hospital of Xi' an Jiaotong University, Xi'an, 710061 Shannxi, China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D064791:Desoxycorticosterone Acetate / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics* / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D009569:Nitric Oxide; D064791:Desoxycorticosterone Acetate; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: deoxycorticosterone acetate (DOCA)-salt; endothelial dysfunction; endothelial nitric oxide synthase (eNOS); hypertension; peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)