Morphine Reduces Myocardial Infarct Size via Heat Shock Protein 90 in Rodents

Abstract EN

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.