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Reciprocal expression of MRTF‐A and myocardin is crucial for pathological vascular remodelling in mice
Author(s) -
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
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.296
Subject(s) - medicine , library science , political science , computer science
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.