Abstract 4829: Dietary Supplementation of Nitrate Protects Against Doxorubicin-Induced Ventricular Dysfunction and Cardiomyocyte Cell Death in Mice
Doxorubicin (DOX) is an effective and broad-spectrum chemotherapeutic agent for cancer. However, its clinical use is limited because of its serious dose-dependent cardiotoxicity. Nitrate (NaNO3) has emerged as an endogenous signaling molecule with potential therapeutic implications for cardiovascular disease. Recent studies have shown that dietary supplementation of nitrate could attenuate myocardial ischemia-reperfusion injury. To this context, we hypothesize that nitrate supplementation may also protect against ventricular dysfunction resulting from DOX-induced cardiomyopathy. Adult male CF-1 outbred mice were administered a single dose of DOX (15 mg/kg, i.p.) and ventricular contractile function was assessed 5 days later. In Nitrate+DOX group, nitrate was added into the drinking water (concentration 1 g/L) begining 7 days before DOX injection and continued throughout the post-DOX treatment period. Five days later, echocardiography was performed for measuring ejection fraction (EF) and fraction shortening (FS). Under surgical anesthesia, a microtip pressure-volume Millar catheter transducer was inserted into the right carotid artery and advanced into the left ventricle to obtain additional functional indices in the same animals. As summarized in Table 1⇓, the ventricular functional parameters were significantly improved in Nitrate+DOX group as compared with DOX group. Furthermore, cardiomyocytes isolated from the CF-1 mice receiving nitrate supplement had significantly less necrotic (22.4±0.6%) and apoptotic (2.0±0.4%) cell death as compared with the control mice (necrosis 37.5±0.6%; apoptosis 3.1±0.2%), following 18 hours incubation with 1 μM DOX. These studies provide the first evidence for the role of nitrate in attenuation of DOX-induced ventricular dysfunction and cardiomyocyte death. We propose that nitrate may be a promising therapeutic agent against cardiotoxicity of DOX.
This research has received full or partial funding support from the American Heart Association, AHA National Center.