PGC-1α limits angiotensin II-induced rat vascular smooth muscle cells proliferation via attenuating NOX1-mediated generation of reactive oxygen species

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-1 alpha [PPAR gamma (peroxisome-proliferator-activated receptor gamma) co-activator-1 alpha] is involved in the regulation of ROS generation, VSMC proliferation and energy metabolism. The aim of the present study was to investigate whether PGC-1 alpha mediates AngII-induced ROS generation and VSMC hyperplasia. Our results showed that the protein content of PGC-1 alpha was negatively correlated with an increase in cell proliferation and migration induced by AngII. Overexpression of PGC-1 alpha inhibited AngII-induced proliferation and migration, ROS generation and NADPH oxidase activity in VSMCs. Conversely, Ad-shPGC-1 alpha (adenovirus-mediated PGC-1 alpha-specific shRNA) led to the opposite effects. Furthermore, the stimulatory effect of Ad-shPGC-1 alpha 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-1 alpha. However, we found that overexpression of PGC-1 alpha 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-1 alpha on NADPH oxidase activity. Our data support a critical role for PGC-1 alpha in the regulation of proliferation and migration of VSMCs, and provide a useful strategy to protect vessels against atherosclerosis.