Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor‐Erythroid 2‐Related Factor 2 (Nrf2)‐Dependent Signaling in Chronic Heart Failure

Background Bioavailability of nitric oxide ( NO ) and hydrogen sulfide (H 2 S) is reduced in heart failure ( HF ). Recent studies suggest cross‐talk between NO and H 2 S signaling. We previously reported that sodium nitrite (Na NO 2 ) ameliorates myocardial ischemia‐reperfusion injury and HF. Nuclear factor‐erythroid‐2‐related factor 2 (Nrf2) regulates the antioxidant proteins expression and is upregulated by H 2 S. We examined the Na NO 2 effects on endogenous H 2 S bioavailability and Nrf2 activation in mice subjected to ischemia‐induced chronic heart failure (CHF). Methods and Results Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. Na NO 2 (165 μg/kgic) or vehicle was administered at reperfusion and then in drinking water (100 mg/L) for 4 weeks. Left ventricular (LV), ejection fraction (EF), LV end diastolic ( LVEDD ) and systolic dimensions ( LVESD ) were determined at baseline and at 4 weeks of reperfusion. Myocardial tissue was analyzed for oxidative stress and respective gene/protein‐related assays. We found that Na NO 2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia‐induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in Na NO 2 ‐treated mice as compared to vehicle, suggesting a reduction in oxidative stress. Na NO 2 therapy markedly increased expression of Cu,Zn‐superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, Na NO 2 upregulated the activity of Nrf2, as well as H 2 S‐producing enzymes, and ultimately increased H 2 S bioavailability in ischemia‐induced CHF in mice as compared with vehicle. Conclusions Our results demonstrate that Na NO 2 therapy significantly improves LV function via increasing H 2 S bioavailability, Nrf2 activation, and antioxidant defenses.