Abstract 3811: Targeting Maladaptive Cardiac Autophagy With HDAC Inhibition
Introduction: Autophagy is an evolutionarily ancient process of protein and organelle recycling that provides energy and resources critical for the survival of post-mitotic cells. However, autophagy can also be maladaptive, and increased autophagy contributes to pathological cardiac remodeling under conditions such as hemodynamic stress. Histone deacetylases (HDACs) play a major role in governing cardiac growth, and pharmacological suppression of HDACs blunts load-induced cardiac hypertrophy. We set out to determine whether alterations in stress-induced maladaptive hypertrophy contribute to the cardioprotective effects of HDAC inhibitor (HDACi) therapy.
Methods: Load-induced cardiac hypertrophy was induced by transverse aortic constriction (TAC). After surgery, mice were randomized to treatment with trichostatin A (TSA), a broad-spectrum HDACi, or vehicle injection. Cardiac function and mass were monitored, and levels of autophagy were quantified. Neonatal rat ventricular myocytes (NRVMs) were studied in vitro to test HDAC-dependent mechanisms in agonist-induced hypertrophy.
Results: TSA markedly blunted the activation of autophagy in pressure-stressed hearts (measured by LC3 processing and recruitment of GFP-LC3 to autophagosomes) while blocking hypertrophic growth by 35% (±4, p<0.01, n=5). To test whether HDACi targets maladaptive autophagy, we studied animals with amplified autophagic responsiveness due to cardiomyocyte-specific over-expression of Beclin 1, a protein involved in early autophagosome formation (Beclin 1 Tg). As expected, Beclin 1 Tg mice manifested increased autophagic activity in the setting of pressure stress and an exaggerated growth response to TAC (75%±3 vs 37%±6 WT, p<0.05). Treatment with TSA nearly abolished the autophagic response, significantly blunted load-induced growth (decreased 80%±4, p<0.001, n=7), and blunted myocardial dysfunction (%FS 70%±3 TSA n=5 vs 45%±3 Veh, n=5). Phenylephrine (PE)-triggered hypertrophy in NRVM was blocked by a panel of structurally distinct HDAC inhibitors, and PE-induced autophagy was diminished 90% (±6, p<0.001, n=5) by HDACi.
Conclusion: HDACi blocks cardiac hypertrophy, at least in part, by suppressing stress-induced maladaptive autophagy.
This research has received full or partial funding support from the American Heart Association, South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).