Nitrite Therapy Improves Left Ventricular Function During Heart Failure via Restoration of Nitric Oxide (NO) Mediated Cytoprotective Signaling
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 (MI/R) injury.
Objective: No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity following pressure overload-induced hypertrophy.
Methods and Results: Serum from heart failure patients exhibited significantly decreased nitrosothiol and cGMP levels. TAC was performed in mice at 10-12 weeks of age. Sodium nitrite (50 mg/L) or saline vehicle (VEH) was administered daily in the drinking water post-operative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks post TAC to assess left ventricular dimensions and ejection fraction (LVEF). We observed increased cardiac nitrite, RXNO, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved LVEF and improved LV dimensions) at 9 weeks (p < 0.001 vs. VEH). In addition, circulating and cardiac brain natriuretic peptide (BNP) levels were attenuated in mice receiving nitrite (p < 0.05 vs. VEH). Western blot analyses revealed upregulation of Akt-eNOS-NO-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.
- left ventricular function
- heart failure
- nitric oxide
- hypertrophic cardiomyopathy
- nitric oxide synthase
- Received March 31, 2013.
- Revision received March 3, 2014.
- Accepted March 4, 2014.