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: Takeya Minami, Koichiro Kuwahara, Yasuaki Nakagawa, Minoru Takaoka, Hideyuki Kinoshita, Kazuhiro Nakao, Yoshihiro Kuwabara, Yuko Yamada, Chinatsu Yamada, Junko Shibata, Satoru Usami, Shinji Yasuno, Toshio Nishikimi, Kenji Ueshima, Masataka Sata, Hiroyasu Nakano, Takahiro Seno, Yutaka Kawahito, Kenji Sobue, Akinori Kimura, Ryozo Nagai, Kazuwa Nakao
• Journal: The EMBO journal (EMBO J) Vol. 31 Issue 23 Pg. 4428-40 (Nov 28 2012) ISSN: 1460-2075 [Electronic] England
• PMID: 23103763 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mrtfa protein, mouse
• Nuclear Proteins
• Serum Response Factor
• Trans-Activators
• myocardin

Topics

• Animals
• Atherosclerosis (pathology)
• COS Cells
• Cell Movement
• Cells, Cultured
• Chlorocebus aethiops
• Femoral Artery (pathology)
• Immunohistochemistry (methods)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Muscle, Smooth, Vascular (metabolism)
• NIH 3T3 Cells
• Neointima (pathology)
• Nuclear Proteins (biosynthesis)
• RNA Interference
• Serum Response Factor (metabolism)
• Signal Transduction
• Time Factors
• Trans-Activators (biosynthesis)
• Wound Healing