1. Endothelial MRTF-A mediates angiotensin II induced cardiac hypertrophy.
- Author
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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, and Xu, Yong
- Subjects
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ENDOTHELIAL cells , *ANGIOTENSIN II , *HYPERTROPHY , *HEART physiology , *TRANSCRIPTION factors - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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