Abstract 10490: Induction of Myocardin-Related Transcription Factor-A Contributes to the Phenotypic Alteration of Vascular Smooth Muscle Cells and Plays a Pivotal Role in Vascular Remodeling
Myocardin-related transcription factor (MRTF)-A is a Rho signaling-responsive co-activator of SRF. Here we evaluated roles played by MRTF-A in vascular remodeling by using mouse models. In femoral arteries injured by wire, expression of MRTF-A was significantly increased compared to that in control arteries, whereas the expression of myocardin was reciprocally decreased. In MRTF-A-/- mice, neointimal formation induced by wire injury in femoral arteries was significantly smaller than that in MRTF-A+/+ mice. MRTF-A expression was also increased in aortic tissues containing diet-induced atherosclerotic lesions in ApoE-/- mice compared to that in normal aortic tissues.Diet-induced atherosclerotic lesions in MRTF-A-/-;ApoE-/- mice was significantly smaller than those in MRTF-A+/+;ApoE-/- mice. The expression of vinculin and MMP-9 genes, which are targets of SRF and are key regulators of cellular migration, was significantly decreased in injured arteries in MRTF-A-/- mice, compared to that in injured arteries in MRTF-A+/+ mice. Indeed, the promoter activity of vinculin gene was controlled by MRTF-A in rat aortic vascular smooth muscle cells (VSMCs). Knocking down MRTF-A in VSMCs resulted in a decrease in the expression of vinculin and MMP-9 genes, and in a significant impairment in PDGF-BB-induced migration capacity. We found that MRTF-A gene expression in VSMCs is controlled by microRNA-1, whose expression is regulated by SRF, and is decreased in de-differentiated VSMCs concomitantly with a decrease in myocardin expression. Furthermore, we demonstrated that treatment with a small molecule inhibitor of MRTF-A, CCG1423 significantly reduced neointimal formation following wire injury in femoral arteries in mice. Collectively, these results demonstrate that MRTF-A induced by down-regulation of miR-1 in de-differentiated VSMCs plays a key role in vascular remodeling by maintaining SRF activity essential to migrate in response to extracellular stimuli. Our study suggests that reciprocal expression of myocardin and MRTF-A contributes to the phenotypic alteration of VSMCs during vascular remodeling and defines MRTF-A as a potentially novel therapeutic target in the treatment of vascular proliferating diseases.
- © 2011 by American Heart Association, Inc.