title: Nitrite Therapy Ameliorates Myocardial Dysfunction via H2S and Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2)-Dependent Signaling in Chronic Heart Failure.
abstract: Bioavailability 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 (NaNO2) 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 NaNO2 effects on endogenous H2S bioavailability and Nrf2 activation in mice subjected to ischemia-induced chronic heart failure (CHF).
  
  
  
  Mice underwent 60 minutes of left coronary artery occlusion and 4 weeks of reperfusion. NaNO2 (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 NaNO2 therapy preserved LVEF, LVEDD and LVSD at 4 weeks during ischemia-induced HF. Myocardial malondialdehyde and protein carbonyl content were significantly reduced in NaNO2-treated mice as compared to vehicle, suggesting a reduction in oxidative stress. NaNO2 therapy markedly increased expression of Cu,Zn-superoxide dismutase, catalase, and glutathione peroxidase during 4 weeks of reperfusion. Furthermore, NaNO2 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.
  
  
  
  Our results demonstrate that NaNO2 therapy significantly improves LV function via increasing H2S bioavailability, Nrf2 activation, and antioxidant defenses.
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Erminia
authors.initials: E
authors.lastname: Donnarumma
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Bradley
authors.affiliation: Department of Surgery, Kurume University School of Medicine Kurume, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otsuka
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Erinn L
authors.initials: EL
authors.lastname: Donnelly
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
authors.affiliation: Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA kisla1@lsuhsc.edu.
authors.forename: Kazi N
authors.initials: KN
authors.lastname: Islam
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054059:Coronary Occlusion / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism*; D006862:Hydrogen Sulfide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D012977:Sodium Nitrite / Q000494:pharmacology*; D013318:Stroke Volume / Q000502:physiology
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; D051267:NF-E2-Related Factor 2; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D012977:Sodium Nitrite; D006862:Hydrogen Sulfide
keywords: H2S; Nrf2; antioxidant; heart failure; nitric oxide; reactive oxygen species