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Author Notes:

Address for correspondence: Dr. David J. Lefer, LSU Cardiovascular Center of Excellence, LSU Health Sciences Center, New Orleans, LA 70112, Tel: (504) 568-2109, Fax: (504) 568-2135, Email: E-mail dlefe1@lsuhsc.edu

SB and KK has contributed equally

We thank Bradley Schwartz, Nabil Sabbak and Benjamin Hayes for their entire expert technical help during the course of these experimental studies.

D.J.L. has served on the Scientific Advisory Board of Theravasc, Inc. Theravasc is currently developing novel nitrite formulations for the treatment of peripheral arterial disease (PAD) and cardiovascular diseases.

Subjects:

Research Funding:

This work was supported by grants from the National Heart, Lung, and Blood Institute (National Institutes of Health; 5R01HL092141, 5R01HL093579, 1U24HL 094373, and 1P20HL113452 to Dr. Lefer and 5R01HL098481 to Dr. Calvert).

This research was also supported by a research grant from the American Diabetes Association, ADA grant 1-12-BS212, to Dr. Ya-xiong Tao, Ph.D.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cardiac & Cardiovascular Systems
  • Hematology
  • Peripheral Vascular Disease
  • Cardiovascular System & Cardiology
  • CARDIAC & CARDIOVASCULAR SYSTEMS
  • HEMATOLOGY
  • PERIPHERAL VASCULAR DISEASE
  • cardiomyopathy
  • hypertrophic
  • cyclic GMP
  • heart failure
  • nitric oxide
  • nitric oxide synthase
  • ventricular function
  • left
  • ISCHEMIA-REPERFUSION INJURY
  • CARDIOMYOCYTE-SPECIFIC OVEREXPRESSION
  • CARDIAC-HYPERTROPHY
  • MYOCARDIAL-INFARCTION
  • PRESSURE-OVERLOAD
  • IN-VIVO
  • FAILING HEART
  • CELL-DEATH
  • SYNTHASE
  • PROTECTS

Nitrite Therapy Improves Left Ventricular Function During Heart Failure via Restoration of Nitric Oxide-Mediated Cytoprotective Signaling

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Journal Title:

Circulation Research

Volume:

Volume 114, Number 8

Publisher:

, Pages 1281-1291

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Rationale: 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. Methods and 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. © 2014 American Heart Association, Inc.

Copyright information:

© 2014 American Heart Association, Inc.

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