title: MRTF-A steers an epigenetic complex to activate endothelin-induced pro-inflammatory transcription in vascular smooth muscle cells.
abstract: Endothelin (ET-1) was initially identified as a potent vasoconstrictor contributing to the maintenance of vascular rhythm. Later studies have implicated ET-1, when aberrantly up-regulated within the vasculature, in a range of human pathologies associated with disruption of vascular homeostasis. ET-1 has been shown to invoke strong pro-inflammatory response in vascular smooth muscle cells (VSMCs); the underlying mechanism, however, remains elusive. Here, we report that the transcriptional modulator MRTF-A mediates the activation of pro-inflammatory mediators by ET-1 in VSMCs. ET-1 increased nuclear enrichment and activity of MRTF-A in cultured VSMCs. MRTF-A silencing attenuated ET-1 induced synthesis and release of pro-inflammatory mediators including IL-6, MCP-1 and IL-1 likely as a result of diminished NF-κB activity. In addition, MRTF-A was indispensible for the accumulation of active histone modifications on the gene promoters. Of intrigue, MRTF-A interacted with and recruited ASH2, a component of the mammalian histone methyltransferase complex, to transactivate pro-inflammatory genes in response to ET-1 treatment. The chromatin remodeling proteins BRG1 and BRM were also required for ET-1-dependent induction of pro-inflammatory mediators by communicating with ASH2, a process dependent on MRTF-A. In conclusion, our data have identified a novel epigenetic complex responsible for vascular inflammation inflicted by ET-1.
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, Jiangsu 210029, China.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Tian
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Bisheng
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology and Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 210029, China yxu2005@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004265:DNA Helicases / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: D019332:Endothelin-1; D006657:Histones; D018836:Inflammation Mediators; C511173:Mrtfa protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C557977:myocardin-related transcription factor-A, rat; D004265:DNA Helicases