Inhibition of Class I HDACs Blunts Cardiac Hypertrophy via TSC2-Dependent mTOR Repression
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Stress-induced pathological hypertrophy is observed in most forms of heart disease. If left unchecked, pathological remodeling can lead to heart failure. Histone deacetylases (HDACs) participate in the progression of pathological cardiac growth, and small molecule inhibitors of HDACs can both reduce and regress pathological hypertrophy. The mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of cell growth. It has been shown that mTORC1 is active during cardiac hypertrophy, leading to increased protein synthesis. Inhibiting mTORC1 can repress pathological remodeling. Interestingly, pan-HDAC inhibitors target mTOR activity in some cancer models. Therefore, we hypothesized that class I HDACs regulate cardiac hypertrophy in an mTOR-dependent manner. To test this hypothesis, neonatal rat ventricular myocytes (NRVMs) were exposed to a variety of growth stimuli, and class I HDACs were inhibited by either pharmacological means or by knockdown of individual HDAC isoforms. We found that HDAC1, HDAC2 and HDAC3 act together to facilitate pathological and physiological cardiomyocyte hypertrophy. In addition, inhibition of class I HDACs decreases mTOR activation by hypertrophic growth stimuli. HDAC inhibition also decreased mTOR activity in the setting of pressure overload using an in vivo surgical model of transverse aortic constriction (TAC). Adult mice with conditional cardiomyocyte-specific knockout of both HDAC1 and HDAC2 together had improved function following TSC surgery as well as decreased mTOR activity. Tuberin (TSC2) is a component of the tuberin-hamartin complex, which inhibits mTOR. We found that inhibition of class I HDACs by either genetic knockdown or using small molecules increased expression of TSC2 in both NRVMs and embryonic stem cell-derived cardiomyocytes. Furthermore, using siRNA we observed that TSC2 is required for HDAC-dependent inhibition of mTOR in NRVMs. These findings point to mTOR, and TSC2-dependent control of mTOR, as critical components of the mechanism through which HDAC inhibitors blunt pathological cardiac growth. Together, these results enhance our understanding of the function of HDACs in cardiac pathology and facilitate the ultimate translational application of HDAC inhibitors in the treatment of heart disease.