Abstract 30: Reciprocal Expression of MRTF-A and Myocardin Mediated by miR-1 Is Crucial for Phenotypic Modulation of Vascular Smooth Muscle Cells

Abstract

Myocardin-related transcription factor (MRTF)-A is a Rho signaling-responsive co-activator of serum response factor (SRF). Here we show that induction of MRTF-A expression is key to pathological vascular remodeling in mouse models of vascular disease. MRTF-A expression was significantly higher in the wire-injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of ApoE -/- mice than in healthy control tissues, whereas myocardin expression was significantly lower. In addition, neointima formation in wire-injured femoral arteries in MRTF-A knockout ( Mkl1 -/- ) mice and atherosclerotic lesions in Mkl1 -/- ;ApoE -/- mice were both significantly attenuated. Expression of vinculin, MMP-9 and integrin β1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1 -/- mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), a cellular model of dedifferentiated VSMCs, knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs was the downregulation of microRNA-1 concomitant with a decrease in myocardin expression. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. MRTF-A could thus be a novel therapeutic target for the treatment of vascular diseases.