Abstract 16962: Sodium Sulfide Therapy Confers Cardioprotection in the Diabetic Heart by Activating AMP-Activated Protein Kinase
Background: Coronary artery disease remains the principal cause of death in patients with diabetes mellitus. We have found that diabetic mice display exacerbated injury following myocardial ischemia-reperfusion (MI/R) and are resistant to most therapeutic interventions. We have reported that sodium sulfide (Na2S) therapy confers cardioprotection during MI/R in non-diabetic mice. Here we tested the hypothesis that Na2S therapy would limit the extent of myocardial injury following MI/R in diabetic mice by activating AMP-activated protein kinase (AMPK), a metabolite sensing protein kinase that has recently been reported to attenuate ER stress in the setting of MI/R.
Methods and Results: Diabetic mice (db/db, 12 wks of age, n=10/group) were subjected to transient myocardial ischemia for a period of 30 min followed by 24 hr of reperfusion. Na2S (0.1 mg/kg) or saline (vehicle) was administered into the LV lumen at the time of reperfusion. Na2S decreased infarct size (INF) relative to the area-at-risk (AAR) by 20% (p<0.001) compared to the vehicle treated animals. In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, additional groups of mice (n=5/group) were sacrificed during early reperfusion. Hearts were excised and processed for Western blot analysis. These studies revealed that the expression of phosphorylated AMPK was increased after MI/R and that treatment with Na2S augmented this MI/R-induced increase. Further analysis revealed that Na2S therapy reduced the MI/R-induced expression of the ER-stress protein, GRP94. Additionally, a reduction in cleaved caspase-3 expression was observed in the Na2S-treated hearts when compared to vehicle-treated hearts.
Conclusion: These findings provide important information that myocardial AMPK activation by Na2S following MI/R sets into motion events, including GRP94 inhibition, which ultimately lead to cardioprotection.
- © 2012 by American Heart Association, Inc.