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.