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

Background: It has been reported that the induction of heme oxygenase-1 (HO-1) mediated by beta 1-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 beta 1-adrenergic receptor agonist, could inhibit HMGB1 release via beta 1-adrenergic receptor-mediated HO-1 induction and attenuate myocardial ischemia/reperfusion (I/R) injury in rats. Materials and Methods: Anesthetized male rats were pretreated with dobutamine (5 or 10 mu g. 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-kappa B) 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-kappa B 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 beta 1-adrenergic receptor via PI3K and p38 MAPK, which inhibited HMGB1 release and attenuated rat myocardial I/R injury in vivo. (C) 2013 Elsevier Inc. All rights reserved.