Abstract 15894: Chronic Dietary Supplementation of Nitrate Decreases Doxorubicin-Induced Oxidative Stress in Cardiac Mitochondria and Tissues
Background: We previously reported that chronic dietary supplementation of inorganic nitrate reduces left ventricular dysfunction, cardiomyocyte apoptosis, and mitochondrial damage caused by doxorubicin (DOX). It has been well demonstrated that oxidative stress plays a key pathogenic role in DOX-induced cardiotoxicity and mitochondrial electron transport chain is a key source of reactive oxygen species (ROS) generation in cardiomyocytes.
Hypothesis: We tested the novel hypothesis that nitrate supplementation decreases ROS overproduction caused by DOX at both mitochondrial and heart tissue levels.
Methods: Adult male CF-1 mice received one of the following treatments: 1) Saline — 0.2 mL, IP; 2) DOX — a single bolus of 15 mg/kg, IP; 3) Nitrate — NaNO3 in drinking water (1 g/L or 12 mmol/L) for entire 13 days period; and 4) Nitrate+DOX — nitrate was given for 7 days before DOX injection and continued thereafter. Five days after either saline or DOX injection with or without nitrate, the mice were sacrificed and heart tissues collected for isolation of mitochondria or measurement of membrane lipid peroxidation. H2O2 generation were measured with amplex red assay in isolated mitochondria.
Results: DOX treatment dramatically increased H2O2 generation from the damaged mitochondrial electron transport chain with both complex I and complex II substrates. Heart tissue lipid peroxidation was also significantly increased by DOX. The nitrate treatment significantly reduced the excessive oxidative stress. (See the Table below)
Conclusions: Our study has provided novel evidence that chronic oral nitrate supplementation significantly decreased cardiac mitochondrial ROS generation as well as tissue lipid peroxidation caused by DOX. The antioxidant properties of nitrate therapy not only provide a new mechanistic understanding for its cardioprotective effects, but also further underscore its potential clinical usefulness to combat DOX-induced cardiotoxicity.
- © 2010 by American Heart Association, Inc.