Abstract 3825: Chronic Dietary Supplementation of Nitrate Prevents Doxorubicin-Induced Cardiac Mitochondrial Damage
Background: We recently reported that chronic dietary supplementation of nitrate significantly reduced the left ventricular dysfunction and cardiomyocyte necrosis/apoptosis caused by doxorubicin (DOX) - potent anticancer drug. However, the underlying mechanisms for the protection remain unclear. Since mitochondria are the primary sub-cellular targets of DOX-induced cardiotoxicity, we tested the hypothesis if nitrate supplementation would attenuate DOX-induced mitochondrial damage.
Methods & Results: Adult male CF-1 mice were divided into three groups:
Saline [0.2 mL, IP];
DOX [a single bolus of 15 mg/kg, IP], and
Nitrate+DOX - nitrate was added into the drinking water (concentration 1 g/L) started 7 days before DOX injection and continued throughout the post-DOX period.
Five days after the saline or DOX injection, the mice were sacrificed for isolation of cardiac mitochondria. Oxidative phosphorylation (OXPHOS) was measured by the rate of oxygen consumption. Activities of electron transport chain complexes (ETC) were determined in solubilized cardiac tissue. As summarized in Table 1⇓, DOX decreased the rate of OXPHOS as shown by reduced concentration of glutamate + malate, the substrate for complex I. OXPHOS measured using succinate, the substrate for complex II remained unchanged. These results were further supported by DOX-induced decrease in NADH dehydrogenase and complex I enzyme activity. Interestingly, chronic nitrate supplementation significantly preserved the activity of NADH dehydrogenase and complex I, as well as OXPHOS.
Conclusion: The present studies have provided novel evidence indicating that chronic oral nitrate supplementation protects mitochondrial ETC (particularly complex I) against DOX-induced mitochondrial functional defects, which may contribute to the reported attenuation of DOX-induced ventricular dysfunction and cardiomyocyte death by nitrate.