title: Brahma-related gene 1 (Brg1) epigenetically regulates CAM activation during hypoxic pulmonary hypertension.
abstract: OBJECTIVE
  Establishment of an inflammatory milieu following elevated leukocyte adhesion to the vascular endothelium, which is mediated by transcriptional activation of cell adhesion molecules (CAMs), contributes to the pathogenesis of chronic hypoxia-induced pulmonary hypertension (HPH). The epigenetic switch that dictates CAM transactivation in response to hypoxia in endothelial cells leading up to HPH is not fully appreciated.
  
  
  RESULTS
  We report here that brahma-related gene 1 (Brg1) and brahma (Brm), two catalytic components of the mammalian chromatin remodelling complex, were induced in cultured endothelial cells challenged with hypoxia in vitro as well as in pulmonary arteries in an animal model of HPH. Over-expression of Brg1/Brm enhanced, while the depletion of Brg1/Brm attenuated, CAM transactivation and adhesion of leukocytes. Endothelial-specific deletion of Brg1/Brm ameliorated vascular inflammation and HPH in mice. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that hypoxia up-regulated the occupancies of Brg1 and Brm on CAM promoters in a nuclear factor κB (NF-κB) -dependent manner. Finally, Brg1 and Brm activated CAM transcription by altering the chromatin structure surrounding the CAM promoters.
  
  
  CONCLUSIONS
  Our data suggest that Brg1 provides the crucial epigenetic link to hypoxia-induced CAM induction and leukocyte adhesion that engenders endothelial malfunction and pathogenesis of HPH. As such, targeting Brg1 in endothelial cells may yield promising strategies in the intervention and/or prevention of HPH.
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Chongqing 400038, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Chen
authors.forename: Fei
authors.initials: F
authors.lastname: Fang
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Yang
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D018920:Coculture Techniques; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D015815:Cell Adhesion Molecules; D016328:NF-kappa B; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Adhesion molecules; Brg1; Epigenetics; Hypoxic pulmonary hypertension; Transcriptional regulation