Inhibition of class I histone deacetylases blunts cardiac hypertrophy through TSC2-dependent mTOR repression
Author
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Morales, Cyndi R.
Author
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Li, Dan L.
Author
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Pedrozo Cibils, Zully
Author
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May, Herman I.
Author
dc.contributor.author
Jiang, Nan
Author
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Kyrychenko, Viktoriia
Author
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Cho, Geoffrey
Author
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Kim, Soo Young
Author
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Wang, Zhao V.
Author
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Rotter, David
Author
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Rothermel, Beverly A.
Author
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Schneider, Jay W.
Author
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Lavandero González, Sergio
Author
dc.contributor.author
Gillette, Thomas G.
Author
dc.contributor.author
Hill, Joseph A.
Admission date
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2016-07-07T19:53:54Z
Available date
dc.date.available
2016-07-07T19:53:54Z
Publication date
dc.date.issued
2016
Cita de ítem
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Science Signaling Volumen: 9 Número: 422 Número de artículo: ra34 apr 2016
en_US
Identifier
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DOI: 10.1126/scisignal.aad5736
Identifier
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https://repositorio.uchile.cl/handle/2250/139475
General note
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Artículo de publicación ISI
en_US
Abstract
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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.
en_US
Patrocinador
dc.description.sponsorship
NIH
HL-120732
HL-100401
HL-126012
HL-097768
HL-072016
AHA (American Heart Association)
14SFRN20740000
CPRIT (Cancer Prevention and Research Institute of Texas)
RP110486P3
RP110486-AC
RP110486-P5
Leducq Foundation
11CVD04
CONICYT (Comision Nacional de Investigacion Cientifica y Tecnologica), Chile
FONDAP 15130011
AHA
11POST7950051
14SDG18440002