Abstract 20638: Inhibition of HDAC6 Attenuates Chronic Angiotensin Ii-Induced Autophagy
Introduction: It has been shown that autophagy is playing one of the crucial cellular functions, which maintain the cellular homeostasis as well as cardiac hypertrophy, but the mechanism is poorly understood. Studies have shown that over activation of autophagy is not always protective but may cause autophagic cell death. Here we have examined the protective role of HDAC6 inhibitor Tubastatin A (TBSA) during chronic angiotensin II-induced autophagy in human iPSC-derived cardiomyocytes (hiCMCs).
Hypothesis: We hypothesize that TBSA treatment mediated activation of STAT3-Bcl2 is a critical regulator of angiotensin II-induced hiCMCs autophagy and the over expression of HDAC6 in hiCMCs leads to exaggerate angiotensin II-induced autophagy.
Methods and Results: We have evaluated the TBSA treatment mediated effects in the contractility of hiCMCs, cell size and mitochondrial membrane potential in response to angiotensin II-induced autophagy. Our data shows that the functional effect of hiCMCs stimulated with angiotensin II has significantly reduced the beating frequency, whereas treatment with TBSA rescued the beating frequency (Fig. A, B). Furthermore, the angiotensin II-induced hypertrophic effect on hiCMCs is significantly reduced by TBSA treatment (Fig. C). Moreover, the immunostaining with JC1 (marker for Autophagy) shows that the mitochondrial membrane potential significantly reduced in angiotensin II-induced hiCMCs, whereas TBSA treatment maintains the mitochondrial membrane potential (Fig D). Moreover, our electron microscopic analysis revealed a dramatic difference was observed between angiotensin II induced hiCMCs and Angiotensin II-induced hiCMCs treated with TBSA in actin cytoskeletal protein and disorganized sarcomeres.
Conclusions: We report for the first time that the role of HDAC6 in regulation of pathological autophagy, thus can acts as a potential therapeutic target for treatment of chronic heart diseases.
Author Disclosures: S. Rajasingh: None. A. Czirok: None. D.G. Isai: None. S. Samanta: None. T. Cao: None. L. Chen: None. B. Dawn: None. J. Rajasingh: None.
- © 2016 by American Heart Association, Inc.