Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity.
Clinical use of doxorubicin (Adriamycin), an antitumor agent, is limited by its oxyradical-mediated cardiotoxicity. We tested the hypothesis that moderate diet restriction protects against doxorubicin-induced cardiotoxicity by decreasing oxidative stress and inducing cardioprotective mechanisms. Male Sprague-Dawley rats (250-275 g) were maintained on diet restriction [35% less food than ad libitum]. Cardiotoxicity was estimated by measuring biomarkers of cardiotoxicity, cardiac function, lipid peroxidation, and histopathology. A LD(100) dose of doxorubicin (12 mg/kg, ip) administered on day 43 led to 100% mortality in ad libitum rats between 7 and 13 days due to higher cardiotoxicity and cardiac dysfunction, whereas all the diet restricted rats exhibited normal cardiac function and survived. Toxicokinetic analysis revealed equal accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the ad libitum and diet restricted hearts. Mechanistic studies revealed that diet restricted rats were protected due to (1) lower oxyradical stress from increased cardiac antioxidants leading to downregulation of uncoupling proteins 2 and 3, (2) induction of cardiac peroxisome proliferators activated receptor-alpha and plasma adiponectin increased cardiac fatty acid oxidation (666.9+/-14.0 nmol/min/g heart in ad libitum versus 1035.6+/-32.3 nmol/min/g heart in diet restriction) and mitochondrial AMPalpha2 protein kinase. The changes led to 51% higher cardiac ATP levels (17.7+/-2.1 micromol/g heart in ad libitum versus 26.7+/-1.9 micromol/g heart in diet restriction), higher ATP/ADP ratio, and (3) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3, which upregulates cardioprotective JAK/STAT3 pathway. These findings collectively show that moderate diet restriction renders resiliency against doxorubicin cardiotoxicity by lowering oxidative stress, enhancing ATP synthesis, and inducing the JAK/STAT3 pathway.
Mitra
Mayurranjan S
MS
Department of Toxicology, College of Pharmacy, 700 University Avenue, Sugar Hall # 306 B, The University of Louisiana at Monroe, Monroe, LA 71209-0495, USA.
Donthamsetty
Shashikiran
S
White
Brent
B
Latendresse
John R
JR
Mehendale
Harihara M
HM
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D052242:Adiponectin / Q000097:blood; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D004032:Diet; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control; D007473:Ion Channels / Q000235:genetics; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics; D009097:Multienzyme Complexes / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D052242:Adiponectin; D000903:Antibiotics, Antineoplastic; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D047493:PPAR alpha; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D053612:Janus Kinases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C010013:adriamycinol