title: Lack of bcr and abr promotes hypoxia-induced pulmonary hypertension in mice.
abstract: BACKGROUND
  Bcr and Abr are GTPase activating proteins that specifically downregulate activity of the small GTPase Rac in restricted cell types in vivo. Rac1 is expressed in smooth muscle cells, a critical cell type involved in the pathogenesis of pulmonary hypertension. The molecular mechanisms that underlie hypoxia-associated pulmonary hypertension are not well-defined.
  
  
  RESULTS
  Bcr and abr null mutant mice were compared to wild type controls for the development of pulmonary hypertension after exposure to hypoxia. Also, pulmonary arterial smooth muscle cells from those mice were cultured in hypoxia and examined for proliferation, p38 activation and IL-6 production. Mice lacking Bcr or Abr exposed to hypoxia developed increased right ventricular pressure, hypertrophy and pulmonary vascular remodeling. Perivascular leukocyte infiltration in the lungs was increased, and under hypoxia bcr-/- and abr-/- macrophages generated more reactive oxygen species. Consistent with a contribution of inflammation and oxidative stress in pulmonary hypertension-associated vascular damage, Bcr and Abr-deficient animals showed elevated endothelial leakage after hypoxia exposure. Hypoxia-treated pulmonary arterial smooth muscle cells from Bcr- or Abr-deficient mice also proliferated faster than those of wild type mice. Moreover, activated Rac1, phosphorylated p38 and interleukin 6 were increased in these cells in the absence of Bcr or Abr. Inhibition of Rac1 activation with Z62954982, a novel Rac inhibitor, decreased proliferation, p38 phosphorylation and IL-6 levels in pulmonary arterial smooth muscle cells exposed to hypoxia.
  
  
  CONCLUSIONS
  Bcr and Abr play a critical role in down-regulating hypoxia-induced pulmonary hypertension by deactivating Rac1 and, through this, reducing both oxidative stress generated by leukocytes as well as p38 phosphorylation, IL-6 production and proliferation of pulmonary arterial smooth muscle cells.
authors.affiliation: Section of Molecular Carcinogenesis, Division of Hematology/Oncology, and The Saban Research Institute of Children's Hospital, Los Angeles, California, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Dapeng
authors.initials: D
authors.lastname: Gong
authors.forename: Min
authors.initials: M
authors.lastname: Lim
authors.forename: Anna
authors.initials: A
authors.lastname: Arutyunyan
authors.forename: John
authors.initials: J
authors.lastname: Groffen
authors.forename: Nora
authors.initials: N
authors.lastname: Heisterkamp
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000172:deficiency* / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D051562:Proto-Oncogene Proteins c-bcr / Q000172:deficiency* / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: C484145:Abr protein, mouse; D020690:GTPase-Activating Proteins; D015850:Interleukin-6; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr; D048051:p38 Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins