Abstract 17461: The Endothelial Nitric Oxide Synthase Modulator Folic Acid Reduces Acute Doxorubicin-Induced Cardiac Damage and Mortality
BACKGROUND: The use of doxorubicin (DOX) as a very effective antineoplastic agent has been compromised by serious cardiac side effects. Endothelial nitric oxide synthase (eNOS) has an important role in the pathogenesis of DOX-induced cardiotoxicity. This study investigates whether high dose of the eNOS modulator folic acid (FA) attenuates cardiac damage and mortality after DOX administration.
METHODS: C57Bl/6J mice (n= 197) received DOX (1x20 mg/kg, ip) or saline (sham). FA (10 mg/d po) or placebo was administered from 7d before DOX administration until the end of the experiment (10d). Cardiomyocytes disarray and apoptosis were evaluated with desmin- and TUNEL-staining. Superoxide generation was measured using lucigenin-enhanced chemiluminescence (total and NOS-dependent). Electron microscopy (EM) was performed at day 6. Thirty-day mortality was evaluated in male and female mice. Chi square test and ONE-way ANOVA with Bonferroni post hoc test were used for statistical analysis.
RESULTS: Kaplan-Meier survival curves demonstrated a significant reduction of FA on DOX-induced mortality after 30d (females 50% vs 10% DOX+placebo, p<0.01; males 30% vs 10% DOX+placebo, p<0.05). Survival in the sham-groups was as expected 100%. Histological analysis showed desmin disorganization in DOX+placebo (17.33 ± 1.35 AU vs. sham+placebo: 4.36 ± 0.43 AU, p<0.001). DOX+FA significantly blunted this myocytes disarray (8.73 ± 1.26 AU, p<0.001 vs DOX+placebo). TUNEL-positivity was significantly increased after DOX administration (0.65 ± 0.03 AU vs sham+placebo: 0.08 ± 0.01 AU, p<0.001). FA significantly reduced DOX-induced TUNEL positivity (0.18 ± 0.02 AU, p<0.001 vs DOX+placebo). NOS-dependent superoxide generation was significantly increased after DOX administration (517 ± 249.5 AU vs sham+placebo: 123.3 ± 1.8 AU, p<0.01) and FA significantly reduced this (62.9 ± 31.2 AU, p<0.01 vs DOX+placebo). Furthermore, EM demonstrated DOX-induced cardiac damage as verified by autophagy of mitochondria and cytoplasmic material, and degeneration of the cardiomyocytes. FA reduced these degenerative changes.
CONCLUSION: Modulating eNOS might be considered as a new therapeutic approach to reduce DOX-induced acute cardiotoxicity.
- © 2012 by American Heart Association, Inc.