Abstract 12157: HDAC-Dependent Regulation of Pathological Hypertrophy
Introduction: Histone deacetylases (HDACs) participate in pathological cardiac growth and failure, and small molecule inhibitors of HDACs slow, and even regress, pathological hypertrophy. mTOR (mammalian target of rapamycin) is a key molecular sensor-regulator of metabolic state, active during cell growth to promote protein synthesis. We hypothesized that class I HDACs regulate cardiac hypertrophy in an mTOR-dependent manner.
Methods: Neonatal rat ventricular myocytes (NRVMs) in culture were exposed to a variety of growth cues to trigger hypertrophy. To test involvement of mTOR and specific HDAC isoforms, small molecule inhibitors or RNAi-based strategies were employed.
Results: Inhibitors of class I HDACs suppressed mTOR activity and protein synthesis, both at baseline and under hypertrophic conditions. RNAi-based knockdown studies revealed similar effects on mTOR activity only when HDAC1, HDAC2 and HDAC3 were inhibited together, suggesting functional redundancy among these isoforms. Tuberin (TSC2) is a component of the tuberin-hamartin complex which negatively regulates mTOR activity. TSC2 levels increased when class I HDACs were inhibited by genetic knockdown or by small molecules in a manner suggestive of transcriptional control. Furthermore, RNAi knockdown of TSC2 prevented HDAC-dependent inhibition of mTOR activity, pointing to an obligate role for TSC2 in HDAC-dependent governance of cell growth.
Conclusions: These findings point to mTOR, and TSC2-dependent control of mTOR, as critical elements of the molecular circuitry whereby HDAC inhibitors blunt pathological cardiac growth. For the first time, we uncover a molecular signaling axis comprising HDACs, TSC2, mTOR, and myocyte growth. Together, these results enhance our understanding of HDAC activity in cardiac pathology, facilitating translational exploitation of HDAC inhibitors in heart disease.
- © 2013 by American Heart Association, Inc.