PMID- 27048565 OWN - NLM STAT- MEDLINE DCOM- 20161220 LR - 20211203 IS - 1937-9145 (Electronic) IS - 1945-0877 (Linking) VI - 9 IP - 422 DP - 2016 Apr 5 TI - Inhibition of class I histone deacetylases blunts cardiac hypertrophy through TSC2-dependent mTOR repression. PG - ra34 LID - 10.1126/scisignal.aad5736 [doi] AB - 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. CI - Copyright (c) 2016, American Association for the Advancement of Science. FAU - Morales, Cyndi R AU - Morales CR AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Li, Dan L AU - Li DL AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Pedrozo, Zully AU - Pedrozo Z AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. Advanced Center for Chronic Diseases, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile. FAU - May, Herman I AU - May HI AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Jiang, Nan AU - Jiang N AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Kyrychenko, Viktoriia AU - Kyrychenko V AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Cho, Geoffrey W AU - Cho GW AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Kim, Soo Young AU - Kim SY AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Wang, Zhao V AU - Wang ZV AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Rotter, David AU - Rotter D AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Rothermel, Beverly A AU - Rothermel BA AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Schneider, Jay W AU - Schneider JW AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Lavandero, Sergio AU - Lavandero S AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. Advanced Center for Chronic Diseases, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile. FAU - Gillette, Thomas G AU - Gillette TG AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. FAU - Hill, Joseph A AU - Hill JA AD - Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. joseph.hill@utsouthwestern.edu. LA - eng GR - R01 HL097768/HL/NHLBI NIH HHS/United States GR - U01 HL100401/HL/NHLBI NIH HHS/United States GR - R01 HL126012/HL/NHLBI NIH HHS/United States GR - HL-100401/HL/NHLBI NIH HHS/United States GR - HL-097768/HL/NHLBI NIH HHS/United States GR - R01 HL072016/HL/NHLBI NIH HHS/United States GR - HL-126012/HL/NHLBI NIH HHS/United States GR - HL-072016/HL/NHLBI NIH HHS/United States GR - R01 HL120732/HL/NHLBI NIH HHS/United States GR - HL-120732/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160405 PL - United States TA - Sci Signal JT - Science signaling JID - 101465400 RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Peptides, Cyclic) RN - 0 (TSC2 protein, human) RN - 0 (Tsc2 protein, mouse) RN - 0 (Tsc2 protein, rat) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 0 (apicidin) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.5.1.98 (Histone Deacetylase 1) RN - EC 3.5.1.98 (Histone Deacetylase 2) SB - IM MH - Animals MH - Animals, Newborn MH - Blotting, Western MH - Cardiomegaly/genetics/*metabolism MH - Cell Line MH - Cells, Cultured MH - Histone Deacetylase 1/genetics/*metabolism MH - Histone Deacetylase 2/genetics/*metabolism MH - Histone Deacetylase Inhibitors/pharmacology MH - Humans MH - Male MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Myocytes, Cardiac/drug effects/metabolism MH - Peptides, Cyclic/pharmacology MH - RNA Interference MH - Rats, Sprague-Dawley MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/genetics/*metabolism MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/genetics/*metabolism PMC - PMC4836394 MID - NIHMS777472 EDAT- 2016/04/07 06:00 MHDA- 2016/12/21 06:00 PMCR- 2016/04/19 CRDT- 2016/04/07 06:00 PHST- 2016/04/07 06:00 [entrez] PHST- 2016/04/07 06:00 [pubmed] PHST- 2016/12/21 06:00 [medline] PHST- 2016/04/19 00:00 [pmc-release] AID - 9/422/ra34 [pii] AID - 10.1126/scisignal.aad5736 [doi] PST - epublish SO - Sci Signal. 2016 Apr 5;9(422):ra34. doi: 10.1126/scisignal.aad5736.