title: Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling.
abstract: BACKGROUND
  Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury.
  
  
  OBJECTIVE
  No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy.
  
  
  RESULTS
  Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.
  
  
  CONCLUSIONS
  These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.
authors.affiliation: From the LSU Cardiovascular Center of Excellence, LSU Health Sciences Center, New Orleans, LA (S.B., D.J.P., H.O., D.J.L.); Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan (K.K., T.M.); Division of Cardiothoracic Surgery, Department of Surgery, Carlyle Fraser Heart Center (C.K.N., J.W.C.) and Division of Cardiology, Department of Medicine (V.V.G., J.B.), Emory University School of Medicine, Atlanta, GA; and Department of Anatomy, Physiology, and Pharmacology, Auburn University College of Veterinary Medicine, AL (Y.-X.T., H.H.).
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kondo
authors.forename: David J
authors.initials: DJ
authors.lastname: Polhemus
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otsuka
authors.forename: Chad K
authors.initials: CK
authors.lastname: Nicholson
authors.forename: Ya-Xiong
authors.initials: YX
authors.lastname: Tao
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Vasiliki V
authors.initials: VV
authors.lastname: Georgiopoulou
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
mesh_terms: D000368:Aged; D000818:Animals; D001682:Biological Availability; D006152:Cyclic GMP / Q000378:metabolism; D019610:Cytoprotection / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012977:Sodium Nitrite / Q000494:pharmacology / Q000627:therapeutic use*; D013318:Stroke Volume / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D009569:Nitric Oxide; D006152:Cyclic GMP; D012977:Sodium Nitrite
keywords: cardiomyopathy, hypertrophic; cyclic GMP; heart failure; nitric oxide; nitric oxide synthase; ventricular function, left