Abstract 9812: Dietary Supplementation of Nitrite Reduces Chronic Cardiotoxicity of Doxorubicin: Role of Activation of Protein Kinase G and Down-Regulation of Endothelial Nitric Oxide Synthase in Heart

Background: Doxorubicin (DOX) is one of the most effective and commonly used chemotherapeutic agents for cancer. Clinical use of DOX is limited because of its serious dose-dependent cardiotoxicity. We recently demonstrated that oral intake of inorganic nitrate (NaNO3) protects against acute cardiotoxicity of DOX. The present study was designed to further elucidate if dietary supplementation of nitrite (NaNO2) also limits the cardiotoxic effects following chronic, multiple low-dose treatment of DOX. Methods & Results: Adult male CF-1 mice were divided into 4 groups (n=6/group): 1) Saline [0.2 ml, IP]; 2) DOX [3 x weekly IP injection of 5 mg/kg DOX; cumulative dose = 15 mg/kg]; 3) Nitrite - NaNO2 was added into drinking water at concentration of 50 mg/L for entire duration of 32 days; 4) Nitrite+DOX - mice received nitrite-enriched water 7 days before the first DOX injection and throughout the 32-day period. Five days after the last DOX injection, echocardiography and pressure-volume Millar microtip catheterization were performed to assess left ventricular (LV) contractile function and other hemodynamic indices. As shown in the Table below, LV systolic and diastolic function was significantly improved in Nitrite+DOX group as compared with DOX group. Oral nitrite intake augmented plasma level of nitrite, but not nitrate or sum of nitrate+nitrite (NOx). Further molecular studies revealed that nitrite intake enhanced cardiac activity of cGMP-dependent protein kinase (PKG) and reduced expression of endothelial nitric oxide synthase (eNOS) as compared with Saline or DOX (n=3/group). Conclusion: We have provided novel evidence showing that dietary nitrite supplementation reduces cardiotoxicity following chronic DOX treatment. The cardioprotective effect of nitrite may be mediated by the enhanced PKG signaling and the decreased expression of likely uncoupled eNOS in the heart. Nitrite could be a promising therapeutic agent in combating chronic DOX cardiotoxicity.