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Am J Physiol Cell Physiol 297: C645-C653, 2009. First published June 24, 2009; doi:10.1152/ajpcell.00469.2008
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VASCULAR BIOLOGY

PGC-1{alpha} attenuates neointimal formation via inhibition of vascular smooth muscle cell migration in the injured rat carotid artery

Aijuan Qu,1 Changtao Jiang,1 Mingjiang Xu,1 Yan Zhang,2 Yi Zhu,1 Qingbo Xu,3 Chenyu Zhang,2 and Xian Wang1

1Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing; 2Jiangsu Diabetes Center, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; and 3Cardiovascular Division, The James Black Centre, King's College, University of London, London, United Kingdom

Submitted 11 September 2008 ; accepted in final form 16 June 2009

Oxidative stress contributes significantly to the migration of vascular smooth muscle cells (VSMCs), the major pathogenic process of vascular diseases, but the mechanism remains unclear. In the present study, we explored the role of peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}), a major regulator of mitochondrial biogenesis and energy balance, in VSMC migration in vitro and in vivo. Overexpression of PGC-1{alpha} in cultured VSMCs led to a 74.5% reduction of migration activity and mitochondrial ROS generation by the increased expression of antioxidative proteins such as SOD-2 in the mitochondria. The knockdown of PGC-1{alpha} by specific small interfering (si)RNA markedly augmented VSMC migration activity and greatly reduced mitochondrial antioxidative protein expression. Furthermore, knockdown of SOD-2 expression by siRNA greatly reversed the inhibitory effect of PGC-1{alpha} overexpression on VSMC migration. In a rat carotid balloon injury model, adenovirus-mediated overexpression of PGC-1{alpha} greatly reduced neointimal formation (ratio of intima to media: 0.78 ± 0.09 vs. 1.45 ± 0.18 in the adenovirus + green fluorescent protein gene- transfected group). Moreover, the expression of SOD-2 was significantly increased in vivo in local vessels after injury in the PGC-1{alpha}-overexpressing group. These data strongly suggest that PGC-1{alpha} inhibits VSMC migration and neointimal formation after vascular injury in rats, mainly by upregulating the expression of the mitochondrial antioxidant enzyme SOD-2.

restenosis; antioxidants; smooth muscle cells; metabolic syndrome; peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha}


Address for reprint requests and other correspondence: X. Wang, Dept. of Physiology and Pathophysiology, Peking Univ., Beijing 100191, China (e-mail: xwang{at}bjmu.edu.cn) or C. Zhang, Jiangsu Diabetes Center, Key Laboratory of Pharmaceutical Biotechnology, Nanjing Univ., Nanjing 210093, China (e-mail: cyzhang{at}nju.edu.cn).






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