Submitted on September 11, 2008
Revised on June 1, 2009
Accepted on June 16, 2009
PGC-1
Attenuates Neointimal Formation via Inhibition of Vascular Smooth Muscle Cell Migration in the Injured Rat Carotid Artery
Aijuan Qu1, Changtao Jiang1, Mingjiang Xu1, Yan Zhang2, Yi Zhu1, Qingbo Xu3, Chenyu Zhang2, and Xian Wang1*
1 Peking University
2 Nanjing University
3 King's College London, UK
* To whom correspondence should be addressed. E-mail: xwang{at}bjmu.edu.cn.
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-
coactivator-1
(PGC-1), a major regulator of mitochondrial biogenesis and energy balance, in VSMC migration in vitro and in vivo. Overexpression of PGC-1 in cultured VSMCs led to 74.5% reduction of migration activity and mitochondrial reactive oxygen species (ROS) generation by the increased expression of anti-oxidative proteins such as superoxide dismutase-2 (SOD-2) in the mitochondria. The knockdown of PGC-1 by specific small interfering RNA (siRNA) markedly augmented VSMC migration activity and greatly reduced mitochondrial anti-oxidative protein expression. Furthermore, knockdown of SOD-2 expression by siRNA greatly reversed the inhibitory effect of PGC-1 overexpression on VSMC migration. In a rat carotid balloon-injury model, adenovirus-mediated overexpression of PGC-1 greatly reduced neointimal formation (ratio of intima to media 0.78 ± 0.09 vs. 1.45 ± 0.18 in the Ad-GFP group). Moreover, the expression of SOD-2 was significantly increased in vivo in local vessels after injury in the PGC-1-overexpression group. These data strongly suggest that PGC-1 inhibits VSMC migration and neointimal formation after vascular injury in rats, mainly by upregulating the expression of the mitochondrial antioxidant enzyme SOD-2.
