Abstract 15588: Folic Acid Attenuates Acute Doxorubicin-Induced Cardiomyopathy by Modulating Endothelial Nitric Oxide Synthase and Mitochondrial Integrity
Aims: In the pathogenesis of doxorubicin (DOXO)-induced cardiomyopathy, endothelial nitric oxide synthase (eNOS) has a pivotal role. Here we tested the hypothesis that folic acid (FA), as an eNOS modulator, attenuates DOXO-induced cardiomyopathy and mortality.
Methods: Male C57BL/6 mice (n=265) received DOXO (1x 20 mg/kg, ip) or saline (sham). FA (10 mg/d po) or placebo was administered from 7d before DOXO administration until the end of the experiment (10d). Left ventricular (LV) function was measured by echocardiography; atrophy, fibrosis and apoptosis by hematoxylin-eosin, Picro-sirius Red and TUNEL staining, respectively; eNOS uncoupling, activity and S-glutathionylation by co-immunoprecipitation and immunoblotting; superoxide (O2-) production by lucigenin-enhanced chemiluminescence, with or without L-NAME (NOS inhibitor); cardiac NO by Griess reaction; mitochondrial function and morphology by mitochondrial oxygen consumption measurements and electron microscopy, respectively.
Results: DOXO produced 70% mortality (P<0.01 vs sham), while mice receiving DOXO and FA (DOXOFA) had significantly lower mortality (45%; P<0.01). FA ameliorated DOXO-induced LV dysfunction, atrophy, fibrosis, and apoptosis (Table 1). Uncoupling, activity and S-glutathionylation levels of eNOS were restored in DOXOFA, and subsequently lead to a reduction in O2- production, which mainly NOS-dependent, and an increase in cardiac NO. Furthermore, FA attenuated mitochondrial dysfunction and morphological changes.
Conclusion: FA as eNOS modulator might be a new and immediate therapeutic approach to reduce DOXO-induced cardiomyopathy.
Author Disclosures: Y. Octavia: None. G. Kararigas: None. M. de Boer: None. R. Kietadisorn: None. M. Swinnen: None. H. Duimel: None. F.K. Verheyen: None. S. Janssens: None. D.J. Duncker: None. A.L. Moens: None.
- © 2015 by American Heart Association, Inc.