Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice

• Published in: The EMBO journal 2012-11, Vol.31 (23), p.4428-4440
• Main Authors: Minami, Takeya, Kuwahara, Koichiro, Nakagawa, Yasuaki, Takaoka, Minoru, Kinoshita, Hideyuki, Nakao, Kazuhiro, Kuwabara, Yoshihiro, Yamada, Yuko, Yamada, Chinatsu, Shibata, Junko, Usami, Satoru, Yasuno, Shinji, Nishikimi, Toshio, Ueshima, Kenji, Sata, Masataka, Nakano, Hiroyasu, Seno, Takahiro, Kawahito, Yutaka, Sobue, Kenji, Kimura, Akinori, Nagai, Ryozo, Nakao, Kazuwa
• Format: Article
• Language: English
• Subjects: Animals; atherosclerosis; Atherosclerosis - pathology; Blood vessels; Cell adhesion & migration; Cell Movement; Cells, Cultured; Cercopithecus aethiops; COS Cells; EMBO24; Femoral Artery - pathology; Gene expression; Immunohistochemistry - methods; Lesions; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular biology; muscle; muscle, smooth; Muscle, Smooth, Vascular - metabolism; Neointima - pathology; NIH 3T3 Cells; Nuclear Proteins - biosynthesis; Proteins; remodelling; RNA Interference; Rodents; Serum Response Factor - metabolism; Signal Transduction; smooth; Time Factors; Trans-Activators - biosynthesis; Vascular diseases; Wound Healing
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2012.296

Myocardin‐related transcription factor (MRTF)‐A is a Rho signalling‐responsive co‐activator of serum response factor (SRF). Here, we show that induction of MRTF‐A expression is key to pathological vascular remodelling. 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. Both neointima formation in wire‐injured femoral arteries in MRTF‐A knockout ( Mkl1 −/− ) mice and atherosclerotic lesions in Mkl1 −/− ; ApoE −/− mice were significantly attenuated. Expression of vinculin, matrix metallopeptidase 9 (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), 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. 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. Pathological vascular remodelling in arterial lesions such as atherosclerotic plaques coincides with increased expression of the transcription factor MRTF‐A. MRTF‐A loss ameliorates these lesions, reducing the expression of cell migration regulators. MRTF‐A therefore represents a promising therapeutic target for vascular disease.