Dataset Information

Increased phosphorylation-dependent nuclear export of class II histone deacetylases in failing human heart.

ABSTRACT: In the failing human heart (FHH) the induction of a fetal contractile protein gene program is directly and selectively associated with the dilated cardiomyopathy (DCM) phenotype and involves multiple signaling pathways. In response to cardiac stress signals, class II HDACs are subject to phosphorylation dependent nuclear export, which allows for activation of fetal cardiac genes via the transcription factor MEF2. The current study tests the hypothesis that MEF2 activation produced by class II HDAC de-repression is present in the FHH. In this study, human left ventricular tissue from nonfailing and failing adult hearts was analyzed for the presence of MEF2, HDACs 4 and 5. CaMK and HDAC kinase activities were measured in tissue homogenates. In nuclear fractions from failing ventricles, HDAC4 and HDAC5 protein was decreased versus nonfailing controls. MEF2 was not reduced in failing nuclear fractions. CaMK and HDAC kinase activities were increased in failing versus nonfailing hearts. PKCmu (PKD1) activity was increased in nuclear fractions from failing human LVs. These data provide support for decreased nuclear compartment class II HDACs in the FHH, associated with increased activities of kinases known to phosphorylate class II HDACs.

SUBMITTER: Calalb MB

PROVIDER: S-EPMC5350751 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Increased phosphorylation-dependent nuclear export of class II histone deacetylases in failing human heart.

Calalb Mihail B MB McKinsey Timothy A TA Newkirk Scott S Huynh Khai K Sucharov Carmen C CC Bristow Michael R MR

Clinical and translational science 20091001 5

In the failing human heart (FHH) the induction of a fetal contractile protein gene program is directly and selectively associated with the dilated cardiomyopathy (DCM) phenotype and involves multiple signaling pathways. In response to cardiac stress signals, class II HDACs are subject to phosphorylation dependent nuclear export, which allows for activation of fetal cardiac genes via the transcription factor MEF2. The current study tests the hypothesis that MEF2 activation produced by class II HD ...[more]

PMID: 20443916

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Project description:Epigenetic mechanisms like altered histone acetylation may have a crucial role in epileptogenesis. In two mouse models of temporal lobe epilepsy, we investigated changes in the expression of class II histone deacetylases (HDAC), a group of signal transducers that shuttle between nucleus and cytoplasm. Intrahippocampal injection of kainic acid (KA) induced a status epilepticus, development of spontaneous seizures (after 3 days), and finally chronic epilepsy and granule cell dispersion. Expression of class II HDAC mRNAs was investigated at different time intervals after KA injection in the granule cell layers and in sectors CA1 and CA3 contralateral to the site of KA injection lacking neurodegeneration. Increased expression of HDAC5 and 9 mRNAs coincided with pronounced granule cell dispersion in the KA-injected hippocampus at late intervals (14-28 days after KA) and equally affected both HDAC9 splice variants. In contrast, in the pilocarpine model (showing no granule cell dispersion), we observed decreases in the expression of HDAC5 and 9 at the same time intervals. Beyond this, striking similarities between both temporal lobe epilepsy models such as fast decreases in HDAC7 and 10 mRNAs during the acute status epilepticus were observed, notably also in the contralateral hippocampus not affected by neurodegeneration. The particular patterns of HDAC mRNA expression suggest a role in epileptogenesis and granule cell dispersion. Reduced expression of HDACs may result in increased expression of pro- and anticonvulsive proteins. On the other hand, export of HDACs from the nucleus into the cytoplasm could allow for deacetylation of cytoplasmatic proteins involved in axonal and dendritic remodeling, like granule cell dispersion. HDAC 5 and HDAC 9 expression is highly increased in granule cells of the KA-injected hippocampus and parallels granule cell dispersion. Both HDACs are thought to be targeted to the cytoplasm and to act there by deacetylating cytoplasmatic (e.g. cytosceleton-related) proteins.

Dataset Information

Increased phosphorylation-dependent nuclear export of class II histone deacetylases in failing human heart.

Publications

Increased phosphorylation-dependent nuclear export of class II histone deacetylases in failing human heart.

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