Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway.
Doxorubicin (DOX) is one of the most effective chemotherapeutic drugs; however, its incidence of cardiotoxicity compromises its therapeutic index. DOX-induced heart failure is thought to be caused by reduction/oxidation cycling of DOX to generate oxidative stress and cardiomyocyte cell death. Resveratrol (RV), a stilbene found in red wine, has been reported to play a cardioprotective role in diseases associated with oxidative stress. The objective of this study was to test the ability of RV to protect against DOX-induced cardiomyocyte death. We hypothesized that RV protects cardiomyocytes from DOX-induced oxidative stress and subsequent cell death through changes in mitochondrial function. DOX induced a rapid increase in reactive oxygen species (ROS) production in cardiac cell mitochondria, which was inhibited by pretreatment with RV, most likely owing to an increase in MnSOD activity. This effect of RV caused additional polarization of the mitochondria in the absence and presence of DOX to increase mitochondrial function. RV pretreatment also prevented DOX-induced cardiomyocyte death. The protective ability of RV against DOX was abolished when Sirt1 was inhibited by nicotinamide. Our data suggest that RV protects against DOX-induced oxidative stress through changes in mitochondrial function, specifically the Sirt1 pathway leading to cardiac cell survival.
Danz
Elizabeth D Brookins
ED
Center for Cardiovascular Sciences, Albany Medical College, Albany, NY 12208, USA.
Skramsted
Jeremy
J
Henry
Nicholas
N
Bennett
James A
JA
Keller
Rebecca S
RS
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000139:chemically induced / Q000517:prevention & control*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D009536:Niacinamide / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002316:Cardiotonic Agents; D017382:Reactive Oxygen Species; D013267:Stilbenes; D009536:Niacinamide; D004317:Doxorubicin; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D000077185:Resveratrol