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.
Bibliographical noteFunding 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.
© 2014 Elsevier Ltd.
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- Angiotensin II
- Cardiac hypertrophy
- Endothelial cell
- Transcriptional regulation