Histone Methyltransferase SET1 Mediates Angiotensin ?-Induced Endothelin-1 Transcription And Cardiac Hypertrophy In Mice

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 ?(Ang ?)was accompanied by the accumulation of histone H3K4 trimethylation,a prominent histone modification for transcriptional activation,on the endothelin-1 promoter.In the meantime,Ang ? stimulated the expression and the occupancy of Suv,Ez,and Trithorax domain 1(SET1),the 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 ? treatment.Knockdown of SET1 in endothelial cells blocked Ang ?-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 SET 1 epigenetically activates endothelin-1 transcription in endothelial cells,there by contributing to Ang ?-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.