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

Abstract

BackgroundBioavailability of nitric oxide (NO) and hydrogen sulfide (H2S) is reduced in heart failure (HF). Recent studies suggest cross‐talk between NO and H2S signaling. We previously reported that sodium nitrite (NaNO 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 H2S. We examined the NaNO 2 effects on endogenous H2S bioavailability and Nrf2 activation in mice subjected to ischemia‐induced chronic heart failure (CHF).Methods and ResultsMice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. NaNO 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 NaNO 2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia‐induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in NaNO 2‐treated mice as compared to vehicle, suggesting a reduction in oxidative stress. NaNO 2 therapy markedly increased expression of Cu,Zn‐superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, NaNO 2 upregulated the activity of Nrf2, as well as H2S‐producing enzymes, and ultimately increased H2S bioavailability in ischemia‐induced CHF in mice as compared with vehicle.ConclusionsOur results demonstrate that NaNO 2 therapy significantly improves LV function via increasing H2S bioavailability, Nrf2 activation, and antioxidant defenses.

Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double‐blind, randomized controlled VaSera trial

“…Another important cause of HF in patients with T2DM is myocardial infarction due to coronary artery disease, with nitrite displaying a potential role in coronary ischaemia–reperfusion injury (IRI) , acute ST‐elevation myocardial infarction (STEMI) and remote ischaemic preconditioning (RIPC) . Moreover, it was shown that chronic, 4–9 weeks' oral sodium nitrite supplementation prevented the increases in end‐diastolic volume (EDV) and end‐systolic volume (ESV) in murine models of IRI following left coronary artery occlusion , and also prevented pressure overload‐induced LV hypertrophy (LVH) with trans‐aortic constriction .…”

The effects of hyperoxia liquid regulate cardiopulmonary bypass‑induced myocardial damage through the Nrf2‑ARE signaling pathway

“…The Nrf2-ARE signaling pathway is recognized to be the most important endogenous anti-oxidative stress pathway (20). Activation of this pathway can induce the production of antioxidant enzyme and phase II drug metabolic enzyme (21). It plays a vital role in maintaining intracellular redox state, reducing oxidative damage and protecting cell function.…”

Hydrogen Sulfide (H2S)-Releasing Compounds: Therapeutic Potential in Cardiovascular Diseases

“…SPRC is a new type of endogenous H 2 S controlled-release preparation that protects rat HF from left coronary occlusion by maintaining levels of antioxidant molecules such as GSH, CAT, and SOD ( Huang et al, 2013 ). NaNO 2 significantly improved ischemia-induced left ventricular function in CHF mice by increasing H 2 S bioavailability, Nrf2 activation, and antioxidant defense ( Donnarumma et al, 2016b ). In addition, Na 2 S treatment inhibits ischemic heart failure in mice by inhibiting nuclear export of histone deacetylase 4 and apoptotic signaling kinase-1 signaling in a thioredoxin 1 dependent manner ( Nicholson et al, 2013 ).…”