TY - JOUR
T1 - Histone methyltransferase SET1 mediates angiotensin II-induced endothelin-1 transcription and cardiac hypertrophy in mice
AU - Yu, Liming
AU - Yang, Guang
AU - Weng, Xinyu
AU - Liang, Peng
AU - Li, Luyang
AU - Li, Jianfei
AU - Fan, Zhiwen
AU - Tian, Wenfang
AU - Wu, Xiaoyan
AU - Xu, Huihui
AU - Fang, Minming
AU - Ji, Yong
AU - Li, Yuehua
AU - Chen, Qi
AU - Xu, Yong
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/5/27
Y1 - 2015/5/27
N2 - 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.
AB - 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.
KW - cardiomegaly
KW - endothelial cells
KW - endothelin-1
KW - epigenenomics
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U2 - 10.1161/ATVBAHA.115.305230
DO - 10.1161/ATVBAHA.115.305230
M3 - Article
C2 - 25814673
AN - SCOPUS:84933055429
SN - 1079-5642
VL - 35
SP - 1207
EP - 1217
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 5
ER -