Abstract 13792: HDAC Inhibition is Cardioprotective by Blunting Maladaptive Cardiomyocyte Autophagy
Introduction: Autophagy is an evolutionarily conserved, lysosome-dependent mechanism of protein and organelle recycling active in cardiac pathology. Basal autophagy is pro-survival; however, excessive stress-induced autophagy is maladaptive and promotes heart failure. We hypothesized that autophagy is a therapeutic target in heart failure.
Methods: Hypertrophy was induced by transverse aortic constriction (TAC), and histone deacetylase inhibition (HDACi) was achieved using trichostatin A (TSA) or the FDA-approved anti-cancer drug, vorinostat. Ischemia-reperfusion (IR) injury was induced by LAD ligation (45 min) and 24 hr reperfusion.
Results: TAC triggered activation of autophagy as measured by LC3-II levels and GFP-LC3 puncta in alpha-MHC GFP-LC3 transgenics (n=5, p<0.01). In alpha-MHC Beclin 1 transgenic mice, we observed dramatic increases in TAC-induced hypertrophy (2-3-fold vs. WT, n=7-10, p<0.001), rapid declines in systolic function, and an exaggerated stress-induced cardiomyocyte autophagic response. Suppressing the augmented autophagy by TSA abrogated hypertrophy (n=10-13, p<0.001), and systolic function was preserved (n=10-13, p<0.01). These data suggest that autophagy contributes to load-induced cardiac hypertrophy. In cultured neonatal rat ventricular myocytes (NRVMs), knockdown of the autophagy-essential genes ATG5 and Beclin 1 resulted in a diminished hypertrophic response to phenylephrine (PE) or endothelin-1. Vorinostat similarly suppressed PE-induced autophagy in NRVMs (n=4, p<0.001). Vorinostat reduced I/R-induced infarct size in a dose-dependent manner (up to 60% at highest dose, n=3-4, p<0.01), and ventricular systolic function was preserved (n=3-4, p<0.01). Vorinostat blunted ischemia-induced changes in autophagic flux triggered by simulated I/R in NRVMs.
Conclusions: Stress-induced autophagic flux is required for cardiac hypertrophic growth and is detrimental to cardiac function. HDACi reduces infarct size and preserves cardiac function, possibly by regulating cardiomyocyte autophagic flux. In aggregate, these data point to autophagy as a unique cellular target that can be titrated therapeutically to impact the development and progression of heart failure.
- © 2011 by American Heart Association, Inc.