Abstract 14811: Inhibition of Histone Deacetylase-6 (HDAC6) Protects Against Atrial Remodeling Through Derailment of a-Tubulin Proteostasis in Experimental and Human Atrial Fibrillation
Background: AF is characterized by structural remodeling, contractile dysfunction and AF progression. Recent work showed histone deacetylases (HDACs) to cause cardiac remodeling by derailing proteostasis. The role of HDACs in AF is unknown. Here, we investigated the involvement of HDACs in tachycardia-induced atrial remodeling in experimental and clinical AF models.
Methods and Results: Tachypacing of HL-1 atrial cardiomyocytes and the Drosophila pupae heart significantly impaired contractile function (amplitude of Ca2+ transients (CaT) and heart wall contractions, respectively), which was prevented by inhibiting HDAC6 (tubacin) and sirtuins (nicotinamide). Tachypacing activated HDAC6, causing α-tubulin deacetylation and depolymerization, and disrupting microtubular structure. Furthermore, tachypacing-induced contractile dysfunction was completely rescued by dominant negative HDAC6 mutants with loss of deacetylase activity in the second catalytic domain, which bears α-tubulin deacetylase activity (TDAC). To elucidate if HDAC6 inhibition protects against AF remodeling in vivo, dogs were treated with the HDAC6 inhibitor tubastatin (1 mg/kg/day infusion) and subjected to atrial tachypacing (400 bpm, ATP). The ATP-induced increase in AF duration (from 5.8±1.3 to 217±196 s; P<.05) was prevented by tubastatin (6.7±1.5 s). Protective effects of tubastatin against ATP-induced electrical remodeling (APD shortening, ICaL reduction), as well as contractile dysfunction (loss of CaT amplitude, sarcomere contractility) were observed (figure). Atrial tissue from AF patients also showed a significant increase in HDAC6 activity and decrease in acetylated and total α-tubulin.
Conclusions: AF impairs contractile function through HDAC6 activation, derailment of α-tubulin proteostasis and microtubule disruption. In vivo inhibition of HDAC6 protects against AF remodeling, indicating HDAC6 as a promising therapeutic target in clinical AF.
- © 2013 by American Heart Association, Inc.