Antioxidants N‐acetylcysterine and Allopurinol synergistically enhance cardiac HIF‐1α and heme oxygenase‐1 and attenuate Postischemic Myocardial Injury in Diabetic Rats

Abstract

Hypoxia inducible factor 1(HIF) α can reduce myocardial ischemia‐reperfusion injury(MIRI). However, hyperglycemia‐induced oxidative stress may reduce cardiac HIF‐1α and subsequently inhibit heme oxygenase 1 (HO‐1), a down‐stream protein of HIF‐1α that has anti‐ischemic properties. N‐acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce MIRI in diabetes (PLoS One. 2011;6:e23967), but the role of HIF‐1α/HO‐1 in this process in unknown. Control or streptozotocin (STZ)‐induced diabetic rats were untreated (C, D) or treated with NAC (1.5g/kg/day) or ALP (100 mg/kg/day) or their combination (NAC+ALP) for four weeks starting one week after STZ injection. Cardiac and plasma 15‐F2t‐isoprostane (IsoP) were increased in D rats while cardiac HO‐1 and protein expression and activity were reduced, accompanied with reduced cardiac HIF‐1α, and increased post‐ischemic myocardial infarct size (IS) and cellular injury in D rats subjected to 30 minutes of coronary artery occlusion and 2 hours of reperfusion (all P<0.05 D vs. C). NAC+ALP normalized cardiac levels of HO‐1 and HIF‐1α protein expression, prevented the increase in IsoP, and reduced myocardial IS, but these effects of NAC+ALP were cancelled by either the HO‐1 blocker protoporphyrin or the HIF‐1α blocker 2‐Methoxyestradiol. It is concluded that HIF‐1α and HO‐1 activation play an important role in NAC and ALP mediated cardioprotection in diabetes.