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Antioxidants N‐Acetylcysteine and Allopurinol attenuation of postischemic myocardial injury in diabetic rats involve Akt and STAT3 mediated eNOS activation

Hyperglycemia‐induced oxidative stress exacerbates myocardial ischemic reperfusion (MI/R) injury. N‐acetylcysteine (NAC) and allopurinol (ALP) reduced MI/R injury in streptozotocin (STZ)‐induced diabetes (PLoS One. 2011;6:e23967), but the mechanism is unclear. We postulated that NAC and ALP attenuate MI/R injury via PI3k/Akt and Jak2/STAT3 mediated eNOS activation in diabetes. Control (C) or STZ‐induced diabetic (D) rats were untreated or treated with NAC (1.5g/kg/day) or ALP (100 mg/kg/day) or their combination for four weeks starting one week after STZ injection. NAC and ALP synergistically decreased myocardial infarct size in D rats subjected to 30 minutes of coronary artery occlusion and 2 hours reperfusion, and restored phosphorylations of cardiac Akt, STAT3 and eNOS (P<0.05 NAC+ALP vs. D). Exposure of rat cardiomyocytes to high glucose and 45 min hypoxia and 2 hours reoxygenation induced post‐hypoxic cell death reflected as increase of lactate dehydrogenase leakage and reduced cell viability. NAC and ALP synergistically reduced post‐hypoxic cell death and enhanced phosphorylations of Akt, STAT3 and eNOS. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490, respectively attenuated NAC and ALP's protective effects in vivo and in vitro. We conclude that activation of both the PI3K/Akt and the Jak2/STAT3 signaling are involved in NAC and ALP mediated attenuation of MI/R injury in diabetes.