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Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors 总被引:12,自引:0,他引:12
Antos CL McKinsey TA Dreitz M Hollingsworth LM Zhang CL Schreiber K Rindt H Gorczynski RJ Olson EN 《The Journal of biological chemistry》2003,278(31):28930-28937
Postnatal cardiac myocytes respond to stress signals by hypertrophic growth and activation of a fetal gene program. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals. To further define the roles of HDACs in cardiac hypertrophy, we analyzed the effects of HDAC inhibitors on the responsiveness of primary cardiomyocytes to hypertrophic agonists. Paradoxically, HDAC inhibitors imposed a dose-dependent blockade to hypertrophy and fetal gene activation. We conclude that distinct HDACs play positive or negative roles in the control of cardiomyocyte hypertrophy. HDAC inhibitors are currently being tested in clinical trials as anti-cancer agents. Our results suggest that these inhibitors may also hold promising clinical value as therapeutics for cardiac hypertrophy and heart failure. 相似文献
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Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development 总被引:1,自引:0,他引:1 下载免费PDF全文
Chang S McKinsey TA Zhang CL Richardson JA Hill JA Olson EN 《Molecular and cellular biology》2004,24(19):8467-8476
The adult heart responds to stress signals by hypertrophic growth, which is often accompanied by activation of a fetal cardiac gene program and eventual cardiac demise. We showed previously that histone deacetylase 9 (HDAC9) acts as a suppressor of cardiac hypertrophy and that mice lacking HDAC9 are sensitized to cardiac stress signals. Here we report that mice lacking HDAC5 display a similar cardiac phenotype and develop profoundly enlarged hearts in response to pressure overload resulting from aortic constriction or constitutive cardiac activation of calcineurin, a transducer of cardiac stress signals. In contrast, mice lacking either HDAC5 or HDAC9 show a hypertrophic response to chronic beta-adrenergic stimulation identical to that of wild-type littermates, suggesting that these HDACs modulate a specific subset of cardiac stress response pathways. We also show that compound mutant mice lacking both HDAC5 and HDAC9 show a propensity for lethal ventricular septal defects and thin-walled myocardium. These findings reveal central roles for HDACs 5 and 9 in the suppression of a subset of cardiac stress signals as well as redundant functions in the control of cardiac development. 相似文献
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Protein kinases C and D mediate agonist-dependent cardiac hypertrophy through nuclear export of histone deacetylase 5 总被引:13,自引:0,他引:13 下载免费PDF全文
Vega RB Harrison BC Meadows E Roberts CR Papst PJ Olson EN McKinsey TA 《Molecular and cellular biology》2004,24(19):8374-8385
A variety of stress signals stimulate cardiac myocytes to undergo hypertrophy. Persistent cardiac hypertrophy is associated with elevated risk for the development of heart failure. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy and that stress signals neutralize this repressive function by triggering phosphorylation- and CRM1-dependent nuclear export of these chromatin-modifying enzymes. However, the identities of cardiac HDAC kinases have remained unclear. Here, we demonstrate that signaling by protein kinase C (PKC) is sufficient and, in some cases, necessary to drive nuclear export of class II HDAC5 in cardiomyocytes. Inhibition of PKC prevents nucleocytoplasmic shuttling of HDAC5 in response to a subset of hypertrophic agonists. Moreover, a nonphosphorylatable HDAC5 mutant is refractory to PKC signaling and blocks cardiomyocyte hypertrophy mediated by pharmacological activators of PKC. We also demonstrate that protein kinase D (PKD), a downstream effector of PKC, directly phosphorylates HDAC5 and stimulates its nuclear export. These findings reveal a novel function for the PKC/PKD axis in coupling extracellular cues to chromatin modifications that control cellular growth, and they suggest potential utility for small-molecule inhibitors of this pathway in the treatment of pathological cardiac gene expression. 相似文献
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Cardiac hypertrophy is a form of global remodeling, although the initial step
seems to be an adaptation to increased hemodynamic demands. The characteristics
of cardiac hypertrophy include the functional reactivation of the arrested fetal
gene program, where histone deacetylases (HDACs) are closely linked in the
development of the process. To date, mammalian HDACs are divided into four
classes: I, II, III, and IV. By structural similarities, class II HDACs are then
subdivided into IIa and IIb. Among class I and II HDACs, HDAC2, 4, 5, and 9 have
been reported to be involved in hypertrophic responses; HDAC4, 5, and 9 are
negative regulators, whereas HDAC2 is a pro-hypertrophic mediator. The molecular
function and regulation of class IIa HDACs depend largely on the
phosphorylation-mediated cytosolic redistribution, whereas those of HDAC2 take
place primarily in the nucleus. In response to stresses, posttranslational
modification (PTM) processes, dynamic modifications after the translation of
proteins, are involved in the regulation of the activities of those
hypertrophy-related HDACs. In this article, we briefly review 1) the activation
of HDAC2 in the development of cardiac hypertrophy and 2) the PTM of HDAC2 and
its implications in the regulation of HDAC2 activity. [BMB Reports 2015; 48(3):
131-138] 相似文献
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Ali Pedram Mahnaz Razandi Ramesh Narayanan James T. Dalton Timothy A. McKinsey Ellis R. Levin 《Molecular biology of the cell》2013,24(24):3805-3818
The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-β-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-β-Estradiol or estrogen receptor β agonists dipropylnitrile and β-LGND2 comparably suppressed angiotensin II–induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor β (ERβ) gene–deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ERβ. This mechanism potentially supports using ERβ agonists as HDAC modulators to treat cardiac disease. 相似文献
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A dynamic role for HDAC7 in MEF2-mediated muscle differentiation 总被引:14,自引:0,他引:14
Dressel U Bailey PJ Wang SC Downes M Evans RM Muscat GE 《The Journal of biological chemistry》2001,276(20):17007-17013
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Berdeaux R Goebel N Banaszynski L Takemori H Wandless T Shelton GD Montminy M 《Nature medicine》2007,13(5):597-603
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Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC–MEF2 complexes 下载免费PDF全文
Marco Miceli Mariarosaria Conte Lucrezia Manente Alfonso Baldi Antonio De Luca Dante Rotili Sergio Valente Antonello Mai Alessandro Usiello Hinrich Gronemeyer Lucia Altucci 《EMBO reports》2009,10(7):776-782
Histone deacetylase (HDAC) inhibitors are promising new epi‐drugs, but the presence of both class I and class II enzymes in HDAC complexes precludes a detailed elucidation of the individual HDAC functions. By using the class II‐specific HDAC inhibitor MC1568, we separated class I‐ and class II‐dependent effects and defined the roles of class II enzymes in muscle differentiation in cultured cells and in vivo. MC1568 arrests myogenesis by (i) decreasing myocyte enhancer factor 2D (MEF2D) expression, (ii) by stabilizing the HDAC4–HDAC3–MEF2D complex, and (iii) paradoxically, by inhibiting differentiation‐induced MEF2D acetylation. In vivo MC1568 shows an apparent tissue‐selective HDAC inhibition. In skeletal muscle and heart, MC1568 inhibits the activity of HDAC4 and HDAC5 without affecting HDAC3 activity, thereby leaving MEF2–HDAC complexes in a repressed state. Our results suggest that HDAC class II‐selective inhibitors might have a therapeutic potential for the treatment of muscle and heart diseases. 相似文献