title: Proinflammatory stimuli engage Brahma related gene 1 and Brahma in endothelial injury.
abstract: BACKGROUND
  Endothelial dysfunction inflicted by inflammation is found in a host of cardiovascular pathologies. One hallmark event in this process is the aggregation and adhesion of leukocyte to the vessel wall mediated by the upregulation of adhesion molecules (CAM) in endothelial cells at the transcriptional level. The epigenetic modulator(s) of CAM transactivation and its underlying pathophysiological relevance remain poorly defined.
  
  
  OBJECTIVE
  Our goal was to determine the involvement of Brahma related gene 1 (Brg1) and Brahma (Brm) in CAM transactivation and its relevance in the pathogenesis of atherosclerosis.
  
  
  RESULTS
  In the present study, we report that proinflammatory stimuli augmented the expression of Brg1 and Brm in vitro in cultured endothelial cells and in vivo in arteries isolated from rodents. Overexpression of Brg1 and Brm promoted while knockdown of Brg1 and Brm abrogated transactivation of adhesion molecules and leukocyte adhesion induced by inflammatory signals. Brg1 and Brm interacted with and were recruited to the CAM promoters by nuclear factor κB/p65. Conversely, depletion of Brg1 and Brm disrupted the kinetics of p65 binding on CAM promoters and crippled CAM activation. Silencing of Brg1 and Brm also altered key epigenetic changes associated with CAM transactivation. Of intrigue, 17β-estradiol antagonized both the expression and activity of Brg1/Brm. Most importantly, endothelial-targeted elimination of Brg1/Brm conferred atheroprotective effects to Apoe(-/-) mice on a Western diet.
  
  
  CONCLUSIONS
  Our data suggest that Brg1 and Brm integrate various proinflammatory cues into CAM transactivation and endothelial malfunction and, as such, may serve as potential therapeutic targets in treating inflammation-related cardiovascular diseases.
authors: From the State Key Laboratory of Reproductive Medicine, and Atherosclerosis Research Center, Provincial Key Laboratory of Cardiovascular Disease; and Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
authors: Fei
authors: F
authors: Fang
authors: Dewei
authors: D
authors: Chen
authors: Liming
authors: L
authors: Yu
authors: Xin
authors: X
authors: Dai
authors: Yuyu
authors: Y
authors: Yang
authors: Wenfang
authors: W
authors: Tian
authors: Xian
authors: X
authors: Cheng
authors: Huihui
authors: H
authors: Xu
authors: Xinyu
authors: X
authors: Weng
authors: Mingming
authors: M
authors: Fang
authors: Jiliang
authors: J
authors: Zhou
authors: Yuqi
authors: Y
authors: Gao
authors: Qi
authors: Q
authors: Chen
authors: Yong
authors: Y
authors: Xu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D044127:Epigenesis, Genetic; D004958:Estradiol / Q000494:pharmacology; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D057772:Vascular System Injuries / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; D018836:Inflammation Mediators; D016328:NF-kappa B; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D004958:Estradiol; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Brg1; atherosclerosis; endothelial dysfunction; epigenetics; inflammation; transcription
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