title: Morphine Reduces Myocardial Infarct Size via Heat Shock Protein 90 in Rodents.
abstract: Opioids reduce injury from myocardial ischemia-reperfusion in humans. In experimental models, this mechanism involves GSK3β inhibition. HSP90 regulates mitochondrial protein import, with GSK3β inhibition increasing HSP90 mitochondrial content. Therefore, we determined whether morphine-induced cardioprotection is mediated by HSP90 and if the protective effect is downstream of GSK3β inhibition. Male Sprague-Dawley rats, aged 8-10 weeks, were subjected to an in vivo myocardial ischemia-reperfusion injury protocol involving 30 minutes of ischemia followed by 2 hours of reperfusion. Hemodynamics were continually monitored and myocardial infarct size determined. Rats received morphine (0.3 mg/kg), the GSK3β inhibitor, SB216763 (0.6 mg/kg), or saline, 10 minutes prior to ischemia. Some rats received selective HSP90 inhibitors, radicicol (0.3 mg/kg), or deoxyspergualin (DSG, 0.6 mg/kg) alone or 5 minutes prior to morphine or SB216763. Morphine reduced myocardial infarct size when compared to control (42 ± 2% versus 60 ± 1%). This protection was abolished by prior treatment of radicicol or DSG (59 ± 1%, 56 ± 2%). GSK3β inhibition also reduced myocardial infarct size (41 ± 2%) with HSP90 inhibition by radicicol or DSG partially inhibiting SB216763-induced infarct size reduction (54 ± 3%, 47 ± 1%, resp.). These data suggest that opioid-induced cardioprotection is mediated by HSP90. Part of this protection afforded by HSP90 is downstream of GSK3β, potentially via the HSP-TOM mitochondrial import pathway.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Small
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Hsu
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: Gross
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gross
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D008297:Male; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018841:HSP90 Heat-Shock Proteins; D009020:Morphine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3