title: PGC-1α limits angiotensin II-induced rat vascular smooth muscle cells proliferation via attenuating NOX1-mediated generation of reactive oxygen species.
abstract: AngII (angiotensin II)-induced excessive ROS (reactive oxygen species) generation and proliferation of VSMCs (vascular smooth muscle cells) is a critical contributor to the pathogenesis of atherosclerosis. PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-1α] is involved in the regulation of ROS generation, VSMC proliferation and energy metabolism. The aim of the present study was to investigate whether PGC-1α mediates AngII-induced ROS generation and VSMC hyperplasia. Our results showed that the protein content of PGC-1α was negatively correlated with an increase in cell proliferation and migration induced by AngII. Overexpression of PGC-1α inhibited AngII-induced proliferation and migration, ROS generation and NADPH oxidase activity in VSMCs. Conversely, Ad-shPGC-1α (adenovirus-mediated PGC-1α-specific shRNA) led to the opposite effects. Furthermore, the stimulatory effect of Ad-shPGC-1α on VSMC proliferation was significantly attenuated by antioxidant and NADPH oxidase inhibitors. Analysis of several key subunits of NADPH oxidase (Rac1, p22(phox), p40(phox), p47(phox) and p67(phox)) and mitochondrial ROS revealed that these mechanisms were not responsible for the observed effects of PGC-1α. However, we found that overexpression of PGC-1α promoted NOX1 degradation through the proteasome degradation pathway under AngII stimulation and consequently attenuated NOX1 (NADPH oxidase 1) expression. These alterations underlie the inhibitory effect of PGC-1α on NADPH oxidase activity. Our data support a critical role for PGC-1α in the regulation of proliferation and migration of VSMCs, and provide a useful strategy to protect vessels against atherosclerosis.
authors: Department of Geratology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710061, China zhaoqingbin05@126.com.
authors: Qingbin
authors: Q
authors: Zhao
authors: Department of Internal Medicine, Chencang Hospital, Baoji, Shanxi 721300, China.
authors: Junfang
authors: J
authors: Zhang
authors: Department of Geratology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi 710061, China.
authors: Huifang
authors: H
authors: Wang
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D000074624:NADPH Oxidase 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D000804:Angiotensin II; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614712:NOX1 protein, rat
keywords: NADPH; NOX1; PGC-1α; angiotensin II; proliferation; reactive oxygen species