title: Astrocyte overexpression of heme oxygenase-1 improves outcome after intracerebral hemorrhage.
abstract: OBJECTIVE
  Heme oxygenase-1 (HO-1) catalyzes the rate-limiting reaction of heme breakdown and may have both antioxidant and pro-oxidant effects. In previous studies, HO-1 overexpression protected astrocytes from heme-mediated injury in vitro. In the present study, we tested the hypothesis that selective astrocyte overexpression of HO-1 improves outcome after intracerebral hemorrhage.
  
  
  METHODS
  Male and female transgenic mice overexpressing human HO-1 driven by the GFAP promoter (GFAP.HMOX1) and wild-type controls received striatal injections of autologous blood (25 μL). Blood-brain barrier disruption was assessed by Evans blue assay and striatal cell viability by methylthiazolyldiphenyl-tetrazolium bromide assay. Neurological deficits were quantified by digital analysis of spontaneous cage activity, adhesive removal, and elevated body swing tests.
  
  
  RESULTS
  Mortality rate for wild-type mice was 34.8% and was similar for males and females; all GFAP.HMOX1 mice survived. Striatal Evans blue leakage at 24 hours was 23.4±3.2 ng in surviving wild-type mice, compared with 10.9±1.8 ng in transgenics. Perihematomal cell viability was reduced to 61±4% of contralateral at 3 days in wild-type mice, versus 80±4% in transgenics. Focal neurological deficits were significantly reduced and spontaneous cage activity was increased in GFAP.HMOX1 mice.
  
  
  CONCLUSIONS
  Selective HO-1 overexpression in astrocytes reduces mortality, blood-brain barrier disruption, perihematomal cell injury, and neurological deficits in an autologous blood injection intracerebral hemorrhage model. Genetic or pharmacological therapies that acutely increase astrocyte HO-1 may be beneficial after intracerebral hemorrhage.
authors.affiliation: From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.).
authors.forename: Jing
authors.initials: J
authors.lastname: Chen-Roetling
authors.affiliation: From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.).
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.).
authors.forename: Hyman M
authors.initials: HM
authors.lastname: Schipper
authors.affiliation: From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.).
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Regan
authors.affiliation: From the Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (J.C.-R., C.S.R., R.F.R.); and Lady Davis Institute, Jewish General Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (W.S., H.M.S.). Raymond.Regan@jefferson.edu.
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Regan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D002543:Cerebral Hemorrhage / Q000201:enzymology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins
chemical_list: D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C528900:glial fibrillary astrocytic protein, mouse; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: blood–brain barrier; heme oxygenase (decyclizing); ischemic preconditioning; stroke