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: Bryce A Small, Yao Lu, Anna K Hsu, Garrett J Gross, Eric R Gross
• Journal: BioMed research international (Biomed Res Int) Vol. 2015 Pg. 129612 ( 2015) ISSN: 2314-6141 [Electronic] United States
• PMID: 26413502 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• HSP90 Heat-Shock Proteins
• Morphine
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3

Topics

• Amino Acid Sequence
• Animals
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• HSP90 Heat-Shock Proteins (metabolism)
• Heart (drug effects)
• Male
• Molecular Sequence Data
• Morphine (pharmacology)
• Myocardial Infarction (metabolism, pathology)
• Myocardium (pathology)
• Rats
• Rats, Sprague-Dawley