Abstract 12938: Hdac6 and Sirtuin Inhibitors Protect Against Tachypacing-Induced Contractile Dysfunction in in vitro and in vivo Models for Atrial Fibrillation.
Introduction: Atrial Fibrillation (AF) is the most common persistent clinical tachyarrhythmia. Its self-perpetuating nature is due to AF-induced remodeling of cardiomyocytes. Recently, it has been shown that AF induces Ca2+ overload. In turn, the Ca2+ overload activates the Ca2+-CaM-CaMK-HDAC pathway, which is associated with contractile dysfunction in the heart. We assessed the hypothesis that remodeling of cardiomyocytes involves tachypacing-induced activation of histone deacytylases (HDACs). To this end, we investigated the action of HDAC inhibitors on cardiomyocyte contractility.
Methods: HL-1 atrial myocytes were paced at 4 Hz and Ca2+ transients (CaT) were assessed after 9 h. Drosophila Melanogaster was tachypaced (4 Hz) in vivo and reduction in heart rate was assessed after 2 h. Myocytes and flies were pretreated with the following HDAC inhibitors; 100nM TSA (HDAC class I, II and IV), 2mM sodiumbutyrate (HDAC class I and IIa), 10mM nicotinamide (HDAC class III, Sirtuins), 1µM tubacin (HDAC6), 1 µM niltubacin (inactive analogue of tubacin).
Results: Tachypacing caused a significant reduction in CaT (38%±1.3%) in the HL1 myocytes. Treatment with tubacin, nicotinamide and sodiumbutyrate significantly protected against tachypacing-induced CaT reduction (Figure). Both TSA and the inactive analogue niltubacin were not protective. Tachypacing of D. Melanogaster significantly decreased the heart rate by approximately 20 %±2.2%. Treatment with tubacin and nicotinamide significantly protected against heart rate reduction. Sodiumbutyrate, TSA and niltubacin treatment were not protective.
In conclusion: HDAC6 and sirtuin inhibitors protect against tachypacing-induced reductions in CaT and heart rate in in vitro and in vivo models of AF. This demonstrates an important role of epigenetic regulation by HDACs in AF-induced remodeling and thereby indicates their potential as therapeutic targets in clinical AF.
- © 2010 by American Heart Association, Inc.