Background: Objective Myocardin-related transcription factor (MRTF)-A is a Rho signaling-responsive co-activator of serum response factor (SRF). The purpose of this study is to investigate the role of MRTF-A and AQP1 (aquaporin 1) in pathological vascular remodeling.
Methods: MRTF-A, AQP1 and neointima expression was detected both in the wire injured femoral arteries of wild-type mice and the atherosclerotic aortic tissues of ApoE-/- mice. Expression of ICAM-1, matrix metallopeptidase 9 (MMP-9) and integrin β1 were also assayed. The intercourse relationship between the molecules were investigated by interfering RNA and inhibitor assay.
Results: MRTF-A and AQP1 expression were 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. Both in wire-injured femoral arteries in MRTF-A knockout (Mkl1-/-) mice and atherosclerotic lesions in Mkl1-/-; ApoE-/- mice, neointima formation were significantly attenuated and the expression of AQP1 were significantly decreased. Expression of ICAM-1, matrix metallopeptidase 9 (MMP-9) and integrin β1, three SRF targets and key regulators of cell migration, and AQP1 in injured arteries was significantly weaker in Mkl1-/- mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs were the down-regulation of microRNA-300. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice.
Conclusions: MRTF-A could be a novel therapeutic target for the treatment of vascular diseases.