Upregulated cardioprotective mechanisms protect diet restricted rats against doxorubicin‐induced cardiotoxicity

Abstract

The clinical use of doxorubicin (Adriamycin®) is limited by its oxyradical-mediated cardio- and nephrotoxicity. Despite many beneficial health effects of moderate diet restriction (DR), the benefits of DR against drug-induced cardiotoxicity have been sparsely investigated. The objective was to test the hypothesis that moderate DR protects against doxorubicin-induced cardio- and nephrotoxicity and to investigate the cardioprotective mechanisms. Male Sprague-Dawley rats (250–275 g), maintained on DR [35% less than ad libitum (AL) food consumption, 42 days], were challenged with a normally LD100 dose of doxorubicin (DOX, 12 mg/kg, ip, 0.9% NaCl) on day 43. While all AL fed rats died between days 7 to 13, all the DR rats survived. Estimation of serum cardiac troponin-I and creatine kinase-MB, and cardiac tissue malondialdehyde revealed high cardiotoxicity during the 12 day time course in AL fed rats. Histopathology revealed focal rarefaction, loss of cardiac myofibrils, and cytoplasmic vacuolization early, becoming more diffuse as severity increased with time. In contrast, the DR rats showed minimal myocardial degeneration by day 8 and were completely devoid of any cardiotoxicity by serum chemistry by day 12. Cytochrome P450 reductase activity was unchanged by DR, suggesting no decrease in DOX redox cycling. Cardiac tissue catalase activity, ATP, the cardioprotective STAT3, and pSTAT3 were higher in the DR rats. Nephrotoxicity was elevated ~4-fold in the AL rats from day 4 to 12 compared to the DR rats. Thus indicating that, moderate DR renders high resiliency to the cardio- and nephrotoxic outcomes of DOX.