Endothelial MRTF-A mediates angiotensin II induced cardiac hypertrophy

Xinyu Weng, Liming Yu, Peng Liang, Dewei Chen, Xian Cheng, Yuyu Yang, Luyang Li, Ting Zhang, Bisheng Zhou, Xiaoyan Wu, Huihui Xu, Mingming Fang, Yuqi Gao, Qi Chen, Yong Xu

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)23-33
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume80
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported, in part, by grants from the National Basic Science Research 973 Program of China ( 2012CB517503 ), the Natural Science Foundation of China ( 91439106 , 81402550 , 31270805 , 31200645 ), the Natural Science Foundation of Jiangsu Province ( BK2012043 , BK20140906 , BK20141498 ), the Education Commission of Jiangsu Province ( 14KJA31001 ), the Program for New Century Excellent Talents in University of China ( NCET-11-0991 ), the Ministry of Education ( 212059 , 20122323411008 ), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). YX is a Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.

Publisher Copyright:
© 2014 Elsevier Ltd.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

Keywords

  • Angiotensin II
  • Cardiac hypertrophy
  • Endothelial cell
  • Endothelin-1
  • MRTF-A
  • Transcriptional regulation

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