Abstract 13769: Role of FOXO Transcription Factors in the Protective Mechanism by Resveratrol Against Cardiomyopathy in the Dystrophin-deficient Mdx Mouse
Purpose: FOXO transcription factors (FOXO) transcriptionally regulate anti-oxidant and autophagy-related genes and elicit cellular stress resistance. We previously reported that treatment with resveratrol (RSV), an activator of the deacetylase SIRT1, ameliorates cardiomyopathy in the dystrophin-deficient mdx mouse (MDX), a model of Duchenne muscular dystrophy. Since SIRT1 is known to activate FOXO under stress conditions, we hypothesized that FOXO play roles in protection by RSV in the mdx heart.
Methods and Results: In Experiment 1, we analyzed cardiac phenotypes in MDX. At 42-week-old, MDX showed cardiac hypertrophy evaluated by heart weight and echocardiography compared with age-matched C57BL10 mice. Left ventricular (LV) systolic function was preserved in MDX at this age. Dihydroethidium (DHE) staining for analysis of cardiac superoxide anion showed that fluorescence intensity was 4.5-fold higher in MDX than control C57BL10. Immunoblot showed that myocardial p62 and LC3-II levels were increased in MDX at 24-week-old, and this was associated with increased phosphor-S6 level, suggesting impaired autophagy due to mTORC1 activation. In Experiment 2, MDX were divided into untreated (RSV0) and RSV-treated (400 mg/kg chow, RSV400) groups. RSV administration was started at 8-week-old, and mice were sacrificed at 65-week-old. Echocardiography at 62-week-old demonstrated that LV fractional shortening was higher (38±2% vs. 34±1%, P<0.05), IVS thickness was thinner, and end-diastolic LV dimension was smaller in RSV400 than those in RSV0. Compared with untreated MDX, RSV treatment significantly up-regulated cardiac mRNA levels of genes known as FOXO’s targets including anti-oxidant catalase (+2.0-fold), SOD1 (+2.8-fold) and autophagy-related LC3b (+2.5-fold), Bnip3 (+4.1-fold). DHE fluorescence intensity was significantly decreased by 45% by resveratrol treatment. Total cardiac LC3 level was rather decreased in RSV400, suggesting promotion of autophagic flux by RSV. Nuclear FOXO3a level assessed by immunostaining was increased in RSV400 compared with RSV0.
Conclusions: RSV ameliorated cardiomyopathy in the mdx mouse probably by attenuating oxidative stress and restoring autophagy via FOXO3a activation.
Author Disclosures: A. Kuno: None. R. Sebori: None. T. Miura: Honoraria; Modest; Chugai Pharmaceutical, Takeda, Behringer-Ingelheim, Astellas, Otsuka, Bayer, Daiichi-Sankyo. Research Grant; Significant; Chugai Pharmaceutical, Takeda, Astra-Zeneka, Astellas, Novartis, Daiich-Sankyo. Y. Horio: None.
- © 2014 by American Heart Association, Inc.