Endothelial MRTF-A mediates angiotensin II induced cardiac hypertrophy. (March 2015)

• Record Type: Journal Article
• Authors: Weng, Xinyu; Yu, Liming; Liang, Peng; Chen, Dewei; Cheng, Xian; Yang, Yuyu; Li, Luyang; Zhang, Ting; Zhou, Bisheng; Wu, Xiaoyan; Xu, Huihui; Fang, Mingming; Gao, Yuqi; Chen, Qi; Xu, Yong
• Is Part Of: Journal of molecular and cellular cardiology. Volume 80(2015:Mar.)
• Page Start: 23
• Page End: 33
• Publication Date: 2015-03
• Subjects: MRTF-A myocardin related transcription factor A -- Ang II angiotensin II -- ET-1 endothelin -- AP-1 activator protein 1 -- shRNA short hairpin RNA; MRTF-A -- Endothelial cell -- Transcriptional regulation -- Cardiac hypertrophy -- Endothelin-1 -- Angiotensin II; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2014.11.009
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Angiotensin II (Ang II) stimulates endothelin (ET-1) transcription, which contributes to cardiac hypertrophy and fibrosis. We have previously reported that myocardin related transcription factor A (MRTF-A) is indispensable for ET-1 transcription in vascular endothelial cells under hypoxic conditions, indicating that MRTF-A might mediate Ang II-induced pathological hypertrophy. Here we report that Ang II augmented the expression of MRTF-A in cultured endothelial cells and in the lungs of mice with cardiac hypertrophy. Over-expression of MRTF-A enhanced, whereas depletion of MRTF-A attenuated, transcriptional activation of ET-1 gene by Ang II. MRTF-A deficiency ameliorated Ang II induced cardiac hypertrophy and fibrosis in mice paralleling diminished synthesis and release of ET-1. Mechanistically, MRTF-A was recruited to the ET-1 promoter by c-Jun/c-Fos (AP-1) in response to Ang II treatment. Once bound, MRTF-A altered the chromatin structure by modulating histone acetylation and H3K4 methylation on the ET-1 promoter. More importantly, mice with endothelial-specific MRTF-A silencing by lentiviral particles phenocopied mice with systemic MRTF-A deletion in terms of Ang II-induced pathological hypertrophy. In conclusion, we data have unveiled a MRTF-A-containing complex that links ET-1 transactivation in endothelial cells to cardiac hypertrophy and fibrosis by Ang II. Highlights: Ang II activates MRTF-A in vascular endothelial cells. MRTF-A mediates Ang II-induced ET-1 transcription in endothelial cells and in mice. MRTF-A interacts with AP-1 to activate ET-1 transcription in endothelial cells. MRTF-A influences the chromatin structure surrounding the ET-1 gene promoter. Endothelial-specific deletion attenuates Ang II-induced hypertrophy in mice.