Inhibition of class I histone deacetylases blunts cardiac hypertrophy through TSC2-dependent mTOR repressionReport as inadecuate

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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.Nota general

Artículo de publicación ISI

Author: Morales, Cyndi R.; - Li, Dan L.; - Pedrozo Cibils, Zully; - May, Herman I.; - Jiang, Nan; - Kyrychenko, Viktoriia; - Cho, Geoffre



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