title: Dobutamine-mediated heme oxygenase-1 induction via PI3K and p38 MAPK inhibits high mobility group box 1 protein release and attenuates rat myocardial ischemia/reperfusion injury in vivo.
abstract: BACKGROUND
  It has been reported that the induction of heme oxygenase-1 (HO-1) mediated by β1-adrenergic receptor inhibits high mobility group box 1 protein (HMGB1) release and increases the survival rate in cecal ligation and puncture-induced septic mice. The present study aimed to investigate whether dobutamine, a selective β1-adrenergic receptor agonist, could inhibit HMGB1 release via β1-adrenergic receptor-mediated HO-1 induction and attenuate myocardial ischemia/reperfusion (I/R) injury in rats.
  
  
  METHODS
  Anesthetized male rats were pretreated with dobutamine (5 or 10 μg. Kg-1. min-1, intravenous) before ischemia in the absence and/or presence of LY294002 (0.3 mg/Kg), a phosphatidylinositol 3-kinase (PI3K)< inhibitor; SB203580 (1 mg/Kg), a p38 mitogen-activated-protein kinase (P38 mitogen-activated-protein kinase [p38 MAPK]) inhibitor, and zinc protoporphyrin IX ([ZnPPIX], 10 mg/Kg), a HO-1 inhibitor, respectively, and then subjected to ischemia for 30 min followed by reperfusion for 4 h. The myocardial I/R injury and oxidative stress were assessed. Likewise, the expressions of HO-1 protein, nuclear factor kappa B (NF-κB) p65, and HMGB1 were measured by Western blot analysis.
  
  
  RESULTS
  Dobutamine significantly and dose-dependently attenuated myocardial I/R injury, reduced oxidative stress, and caused the induction of HO-1, the reduction of NF-κB activation and HMGB1 over expression. However, all the effects caused by dobutamine were significantly reversed by the presence of LY294002, SB203580, and ZnPPIX, respectively.
  
  
  CONCLUSIONS
  The present study demonstrated that dobutamine mediated the induction of HO-1 by selectively stimulating β1-adrenergic receptor via PI3K and p38 MAPK, which inhibited HMGB1 release and attenuated rat myocardial I/R injury in vivo.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuchang, Wuhan, PR China.
authors.forename: Jichun
authors.initials: J
authors.lastname: Wang
authors.forename: Hongxin
authors.initials: H
authors.lastname: Yang
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Hu
authors.forename: Wenwen
authors.initials: W
authors.lastname: Fu
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.forename: Xiaoya
authors.initials: X
authors.lastname: Zhou
authors.forename: Weipan
authors.initials: W
authors.lastname: Xu
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004280:Dobutamine / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D011524:Protoporphyrins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D002867:Chromones; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D007093:Imidazoles; D009025:Morpholines; D011524:Protoporphyrins; D011725:Pyridines; C017803:zinc protoporphyrin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004280:Dobutamine; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Dobutamine; Heme oxygenase-1; High mobility group box 1 protein; Myocardial ischemia and reperfusion