Research ArticleCardiovascular Biology

Inhibition of class I histone deacetylases blunts cardiac hypertrophy through TSC2-dependent mTOR repression

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Sci. Signal.  05 Apr 2016:
Vol. 9, Issue 422, pp. ra34
DOI: 10.1126/scisignal.aad5736

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Keeping mTORC1 in check in the heart

In response to the increased workload caused by high blood pressure, the cells in the heart expand in size, causing the walls of the heart to thicken. Although this process of cardiac hypertrophy may be initially beneficial, it can lead to heart failure if not restrained. Using cardiomyocytes and mice with surgically induced heart failure, Morales et al. investigated how pathological cardiac hypertrophy is suppressed by inhibitors of histone deacetylases (HDACs), enzymes that remodel chromatin and alter gene expression. They found that these drugs increased the expression of a gene encoding an inhibitor of mTORC1, a multiprotein complex that stimulates cell growth. HDAC inhibitors have been approved to treat various cancers, and these results explain how these drugs could work when repurposed to prevent heart failure.

Abstract

Altering chromatin structure through histone posttranslational modifications has emerged as a key driver of transcriptional responses in cells. Modulation of these transcriptional responses by pharmacological inhibition of class I histone deacetylases (HDACs), a group of chromatin remodeling enzymes, has been successful in blocking the growth of some cancer cell types. These inhibitors also attenuate the pathogenesis of pathological cardiac remodeling by blunting and even reversing pathological hypertrophy. The mechanistic target of rapamycin (mTOR) is a critical sensor and regulator of cell growth that, as part of mTOR complex 1 (mTORC1), drives changes in protein synthesis and metabolism in both pathological and physiological hypertrophy. We demonstrated through pharmacological and genetic methods that inhibition of class I HDACs suppressed pathological cardiac hypertrophy through inhibition of mTOR activity. Mice genetically silenced for HDAC1 and HDAC2 had a reduced hypertrophic response to thoracic aortic constriction (TAC) and showed reduced mTOR activity. We determined that the abundance of tuberous sclerosis complex 2 (TSC2), an mTOR inhibitor, was increased through a transcriptional mechanism in cardiomyocytes when class I HDACs were inhibited. In neonatal rat cardiomyocytes, loss of TSC2 abolished HDAC-dependent inhibition of mTOR activity, and increased expression of TSC2 was sufficient to reduce hypertrophy in response to phenylephrine. These findings point to mTOR and TSC2-dependent control of mTOR as critical components of the mechanism by which HDAC inhibitors blunt pathological cardiac growth. These results also suggest a strategy to modulate mTOR activity and facilitate the translational exploitation of HDAC inhibitors in heart disease.

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