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

• Type of Material: Article
• Authors: Shashi Bhushan, LSU Health Sciences Center; Kazuhisa Kondo, Nagoya University; David Polhemus, LSU Health Sciences Center; Hiroyuki Otsuka, LSU Health Sciences Center; Chad Nicholson, Emory University; Ya-Xiong Tao, Auburn University; Hui Huang, Auburn University; Vasiliki Georgiopoulou, Emory University; Toyoaki Murohara, Nagoya University; John Calvert, Emory University; Javed Butler, Emory University; David J. Lefer, LSU Health Sciences Center
• Language: English
• Date: 2014-03-05
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCRESAHA.114.301475
• Title of Journal or Parent Work: Circulation Research
• ISSN: 0009-7330
• Volume: 114
• Issue: 8
• Start Page: 1281
• End Page: 1291
• Grant/Funding Information: 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.; 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).
• Keywords: FAILING HEART; CARDIAC & CARDIOVASCULAR SYSTEMS; CARDIAC-HYPERTROPHY; Cardiovascular System & Cardiology; hypertrophic; nitric oxide; ISCHEMIA-REPERFUSION INJURY; left; Cardiac & Cardiovascular Systems; CARDIOMYOCYTE-SPECIFIC OVEREXPRESSION; IN-VIVO; Peripheral Vascular Disease; cyclic GMP; MYOCARDIAL-INFARCTION; nitric oxide synthase; PROTECTS; Hematology; heart failure; CELL-DEATH; Life Sciences & Biomedicine; ventricular function; HEMATOLOGY; PERIPHERAL VASCULAR DISEASE; Science & Technology; PRESSURE-OVERLOAD; SYNTHASE; cardiomyopathy
• Research Categories: Biology, Physiology; Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery

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.