Metabolic remodeling associated with subchronic doxorubicin cardiomyopathy
Abstract
Doxorubicin (Adriamycin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is restricted by a cumulative and progressive cardiomyopathy that develops with repeated dosing. Fundamental to the cardiac failure is an interference with mitochondrial respiration and inhibition of oxidative phosphorylation. Global gene expression arrays in cardiac tissue indicate that inhibition of mitochondrial oxidative phosphorylation by doxorubicin (DOX) is accompanied by a decreased expression of genes related to aerobic fatty acid oxidation and a corresponding increase in expression of genes involved in anaerobic glycolysis, possibly as an alternate source for ATP production. The aim of this investigation was to determine whether this is also manifest at the metabonomic level as a switch in metabolic flux in cardiac tissue, and whether this can be averted by co-administering the cardioprotective drug, dexrazoxane (DZR). (13)C-isotopomer analysis of isolated perfused hearts from male Sprague-Dawley rats receiving 6 weekly s.c. injections of 2mg/kg DOX demonstrated a shift from the preferential oxidation of fatty acids to enhanced oxidation of glucose and lactate plus pyruvate, indicative of a compensatory shift to...Continue Reading
Citations
Aspartate facilitates mitochondrial function, growth arrest and survival during doxorubicin exposure
A metabolomic study of rats with doxorubicin-induced cardiomyopathy and Shengmai injection treatment
Editor's Highlight: The Altered DNA Methylome of Chronic Doxorubicin Exposure in Sprague Dawley Rats
Cardiomyocyte-specific disruption of Cathepsin K protects against doxorubicin-induced cardiotoxicity
Disruption of the Keap1/Nrf2-Antioxidant Response System After Chronic Doxorubicin Exposure In Vivo.
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