Abstract 502: Inhibition of Histone Deacetylase 6 Protects Human Induced Pluripotent Stem Cells-derived Cardiomyocytes Through Inhibition of Autophagy

Abstract

Introduction: Autophagy is known to play an important role in mediating cardiac hypertrophy. However, the mechanism is poorly understood. Since the protein histone deacetylase 6 (HDAC6) contributes to cardiac dysfunction in response to angiotensin II (AngII) signaling, we have examined the role of HDAC6 inhibitor tubastatin A (TBA) in AngII-induced remodeling in human induced pluripotent stem cells-derived cardiomyocytes (iCMCs). Hypothesis: We hypothesize that the inhibition of HDAC6 protects iCMCs from AngII-induced cardiac hypertrophy through inhibition of autophagy. Methods and Results: We have generated and characterized induced pluripotent stem cells from human adult skin fibroblasts and subsequently differentiated them into iCMCs. Treatment with 10 μM angiotensin II for 24 hrs increased the HDAC6 activity and lead to hypertrophy in iCMCs. The AngII-induced hypertrophy, and the excessive contractility in iCMCs were reversed by the inhibition of HDAC6 with TBA (1 μM for 24 hours). The number of LC3-positive iCMCs, and the mRNA and the protein expression of autophagic genes Beclin-1, LC3, and p62 were increased by the presence of AngII, and the anti-autophagic gene Bcl2 was decreased by AngII. The inhibition of HDAC6 with TBA reversed the AngII-mediated changes in the autophagic genes expressions in iCMCs. Autophagic vacuoles were identified with monodansylcadaverine (MDC, green) and lysosomes with LysoTracker (red) (Fig. 1A) . The number of autophagolysosomes were increased by AngII, and this was decreased with TBA in iCMCs (Fig. 1B) . Conclusions: Our report indicates for the first time that the AngII-induced cardiac hypertrophy-mediated autophagy is effectively inhibited by the suppression of HDAC6 in human iCMCs.