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.
Highlights
Strategies for mitigating organ damage from ischemia-reperfusion injury during surgical procedures are a continued topic of research for anesthesiologists and surgeons
Prior studies we performed were the first to characterize in rodents the cellular mechanism of opioidinduced cardioprotection, involving δ-opioid receptors [5] and a central role for glycogen synthase kinase 3β (GSK3β) inhibition [6]
We examined the importance of the ATP and tetratricopeptide repeat domain (TPR) domains of heat shock protein 90 (HSP90) and whether inhibition of the ATP or TPR domain affects infarct size reduction afforded by morphine or GSK3β inhibition
Summary
Strategies for mitigating organ damage from ischemia-reperfusion injury during surgical procedures are a continued topic of research for anesthesiologists and surgeons. An experimental model of cardiac ischemia-reperfusion injury is frequently used to study agents, interventions, and molecular mechanisms which reduce myocardial damage. The translation of these models into the operating room, during cardiovascular surgeries such as valve replacements and coronary artery bypass grafting, has produced encouraging strategies to reduce the associated reperfusion injury when an aortic cross-clamp is released, such as ischemic preconditioning, remote conditioning, volatile anesthetics, and opioids. Volatile anesthetics [2], ischemic preconditioning [3], and remote conditioning [4] all involve an opioid receptor-dependent mechanism. Prior studies we performed were the first to characterize in rodents the cellular mechanism of opioidinduced cardioprotection, involving δ-opioid receptors [5] and a central role for glycogen synthase kinase 3β (GSK3β) inhibition [6]
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