title: A crosstalk between chromatin remodeling and histone H3K4 methyltransferase complexes in endothelial cells regulates angiotensin II-induced cardiac hypertrophy.
abstract: Angiotensin II (Ang II) induces cardiac hypertrophy and fibrosis in part by stimulating endothelin (ET-1) transcription. The involvement of the epigenetic machinery in this process is largely undefined. In the present study, we examined the epigenetic maneuvering underlying cardiac hypertrophy and fibrosis following ET-1 transactivation by Ang II. In response to Ang II stimulation, core components of the mammalian chromatin remodeling complex (Brahma-related gene 1, or Brg1, and Brahma or Brm) and histone H3K4 methylation complex (Ash2, absent, small, or homeotic discs 2, or Ash2 and WD domain repeat 5, or Wdr5) were recruited to the ET-1 promoter region in endothelial cells. Over-expression of Brg1/Brm or Ash2/Wdr5 enhanced while depletion of Brg1/Brm or Ash2/Wdr5 attenuated Ang II-induced ET-1 transactivation. Endothelial-specific knockdown of Brg1/Brm or Ash2/Wdr5 ameliorated cardiac hypertrophy both in vitro and in vivo. More important, Brg1/Brm interacted with Ash2/Wdr5 on the ET-1 promoter to catalyze H3K4 methylation. The crosstalk between Brg11/Brm and Ash2/Wdr5 was mediated by myocardin-related transcription factor A (MRTF-A). In conclusion, our data have unveiled an epigenetic complex that links ET-1 transactivation in endothelial cells to Ang II-induced cardiac hypertrophy and fibrosis.
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Weng
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Luyang
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Dai
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Bisheng
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China. Electronic address: mmfangnjmu@yahoo.com.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, Nanjing, China. Electronic address: yxu2005@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002461:Cell Line, Transformed; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D019332:Endothelin-1; C431575:MRTFA protein, human; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000804:Angiotensin II; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: Cardiac hypertrophy; ET-1; Epigenetics; Transcriptional regulation; Vascular endothelial cell