title: Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice.
abstract: 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.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeya
authors.initials: T
authors.lastname: Minami
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Takaoka
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakao
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Yamada
authors.forename: Junko
authors.initials: J
authors.lastname: Shibata
authors.forename: Satoru
authors.initials: S
authors.lastname: Usami
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Nakano
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawahito
authors.forename: Kenji
authors.initials: K
authors.lastname: Sobue
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000473:pathology*; D019556:COS Cells; D002465:Cell Movement; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005263:Femoral Artery / Q000473:pathology; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D041681:NIH 3T3 Cells; D058426:Neointima / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis*; D034622:RNA Interference; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000096:biosynthesis*; D014945:Wound Healing; D000099251:Myocardin
chemical_list: D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin; C511173:Mrtfa protein, mouse