Histone methyltransferase SET1 mediates angiotensin II-induced endothelin-1 transcription and cardiac hypertrophy in mice

Liming Yu, Guang Yang, Xinyu Weng, Peng Liang, Luyang Li, Jianfei Li, Zhiwen Fan, Wenfang Tian, Xiaoyan Wu, Huihui Xu, Minming Fang, Yong Ji, Yuehua Li, Qi Chen, Yong Xu

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Objective - Endothelin-1 is a potent vasoconstrictor derived from vascular endothelium. Elevated endothelin-1 levels are observed in a host of cardiovascular pathologies including cardiomyopathy. The epigenetic mechanism responsible for endothelin-1 induction in these pathological processes remains elusive. Approach and Results - We report here that induction of endothelin-1 expression in endothelial cells by angiotensin II (Ang II) was accompanied by the accumulation of histone H3K4 trimethylation, a preeminent histone modification for transcriptional activation, on the endothelin-1 promoter. In the meantime, Ang II stimulated the expression and the occupancy of Suv, Ez, and Trithorax domain 1 (SET1), a mammalian histone H3K4 trimethyltransferase, on the endothelin-1 promoter, both in vitro and in vivo. SET1 was recruited to the endothelin-1 promoter by activating protein 1 (c-Jun/c-Fos) and synergized with activating protein 1 to activate endothelin-1 transcription in response to Ang II treatment. Knockdown of SET1 in endothelial cells blocked Ang II-induced endothelin-1 synthesis and abrogated hypertrophy of cultured cardiomyocyte. Finally, endothelial-specific depletion of SET1 in mice attenuated Ang II-induced pathological hypertrophy and cardiac fibrosis. Conclusions - Our data suggest that SET1 epigenetically activates endothelin-1 transcription in endothelial cells, thereby contributing to Ang II-induced cardiac hypertrophy. As such, screening of small-molecule compound that inhibits SET1 activity will likely offer a new therapeutic solution to the treatment of cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)1207-1217
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume35
Issue number5
DOIs
StatePublished - May 27 2015
Externally publishedYes

Keywords

  • cardiomegaly
  • endothelial cells
  • endothelin-1
  • epigenenomics

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