title: Histone Methyltransferase SET1 Mediates Angiotensin II-Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice.
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.
  
  
  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.
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Liming
authors: L
authors: Yu
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Guang
authors: G
authors: Yang
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Xinyu
authors: X
authors: Weng
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Peng
authors: P
authors: Liang
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Luyang
authors: L
authors: Li
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Jianfei
authors: J
authors: Li
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Zhiwen
authors: Z
authors: Fan
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Wenfang
authors: W
authors: Tian
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Xiaoyan
authors: X
authors: Wu
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Huihui
authors: H
authors: Xu
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Minming
authors: M
authors: Fang
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Yong
authors: Y
authors: Ji
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Yuehua
authors: Y
authors: Li
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
authors: Qi
authors: Q
authors: Chen
authors: From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.). yxu2005@gmail.com.
authors: Yong
authors: Y
authors: Xu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells; D019332:Endothelin-1 / Q000187:drug effects / Q000235:genetics*; D057890:Epigenomics; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D000804:Angiotensin II; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: cardiomegaly; endothelial cells; endothelin-1; epigenenomics