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

Abstract

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-1alpha (PGC-1alpha), a major regulator of mitochondrial biogenesis and energy balance, in VSMC migration in vitro and in vivo. Overexpression of PGC-1alpha 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-1alpha 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-1alpha overexpression on VSMC migration. In a rat carotid balloon injury model, adenovirus-mediated overexpression of PGC-1alpha 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-1alpha-overexpressing group. These data strongly suggest that PGC-1alpha inhibits VSMC migration and neointimal formation after vascular injury in rats, mainly by upregulating the expression of the mitochondrial antioxidant enzyme SOD-2.

• Authors: Aijuan Qu, Changtao Jiang, Mingjiang Xu, Yan Zhang, Yi Zhu, Qingbo Xu, Chenyu Zhang, Xian Wang
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 297 Issue 3 Pg. C645-53 (Sep 2009) ISSN: 1522-1563 [Electronic] United States
• PMID: 19553562 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Platelet-Derived Growth Factor
• Ppargc1a protein, rat
• Proto-Oncogene Proteins c-sis
• RNA-Binding Proteins
• Reactive Oxygen Species
• Transcription Factors
• Becaplermin
• Superoxide Dismutase
• superoxide dismutase 2

Topics

• Animals
• Aorta (cytology)
• Becaplermin
• Carotid Arteries (cytology)
• Cell Movement
• Cells, Cultured
• Gene Expression Regulation (physiology)
• Immunohistochemistry
• Male
• Mitochondria (metabolism)
• Myocytes, Smooth Muscle (cytology, drug effects, metabolism)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Platelet-Derived Growth Factor (pharmacology)
• Proto-Oncogene Proteins c-sis
• RNA-Binding Proteins (genetics, metabolism)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species
• Superoxide Dismutase (metabolism)
• Transcription Factors (genetics, metabolism)
• Tunica Intima (injuries)