Abstract
Histone deacetylase 5 (HDAC5) and HDAC9 are class IIa HDACs that function as signal-responsive repressors of the epigenetic program for pathological cardiomyocyte hypertrophy. The conserved deacetylase domains of HDAC5 and HDAC9 are not required for inhibition of cardiac hypertrophy. Thus, the biological function of class IIa HDAC catalytic activity in the heart remains unknown. Here we demonstrate that catalytic activity of HDAC5, but not HDAC9, suppresses mitochondrial reactive oxygen species generation and subsequent induction of NF-E2-related factor 2 (NRF2)-dependent antioxidant gene expression in cardiomyocytes. Treatment of cardiomyocytes with TMP195 or TMP269, which are selective class IIa HDAC inhibitors, or shRNA-mediated knockdown of HDAC5 but not HDAC9 leads to stimulation of NRF2-mediated transcription in a reactive oxygen species-dependent manner. Conversely, ectopic expression of catalytically active HDAC5 decreases cardiomyocyte oxidative stress and represses NRF2 activation. These findings establish a role of the catalytic domain of HDAC5 in the control of cardiomyocyte redox homeostasis and define TMP195 and TMP269 as a novel class of NRF2 activators that function by suppressing the enzymatic activity of an epigenetic regulator.
Highlights
Histone deacetylase 5 (HDAC5) and HDAC9 are class IIa histone deacetylases (HDACs) that function as signal-responsive repressors of the epigenetic program for pathological cardiomyocyte hypertrophy
Prior studies demonstrated that ectopic expression of truncated versions of HDAC5 and HDAC9 lacking catalytic domains leads to inhibition of cardiomyocyte hypertrophy [8]
To rule out possible confounding issues related to HDAC overexpression and to corroborate these findings at the level of endogenous class IIa HDACs, cultured neonatal rat ventricular myocytes (NRVMs) were treated with a recently discovered small molecule, TMP195, which selectively inhibits class IIa catalytic activity but does not suppress other HDAC isoforms [15]
Summary
Class IIa HDAC catalytic domain inhibition has no effect on hypertrophy of cardiomyocytes Class IIa HDACs function as signal-responsive repressors of cardiac hypertrophy. TMP195-mediated antioxidant gene expression was attenuated by knockdown on endogenous NRF2, further suggesting that the class IIa HDAC inhibitor stimulates the activity of this transcription factor (Fig. 3, F and G). To begin to address whether TMP195 stimulates NRF2-mediated gene expression via inhibition of class IIa HDAC catalytic activity as opposed to an off-target action, NRVMs were treated with a structurally distinct class IIa HDAC inhibitor, TMP269 [15] (Fig. 3H). Pretreatment of NRVMs with the antioxidant N-acetylcysteine completely blocked TMP195-induced expression of Hmox and Srxn mRNA and reduced the basal levels of these transcripts in unstimulated cardiomyocytes (Fig. 6, D and E) These data suggest that HDAC5 inhibition stimulates NRF2 in cardiomyocytes, at least in part, by triggering oxidative stress. These data further suggest that HDAC5 catalytic activity suppresses cardiomyocyte redox signaling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
