Increased phosphorylation-dependent nuclear export of class II histone deacetylases in failing human heart.
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.
Calalb
Mihail B
MB
University of Colorado Cardiovascular Institute, Denver, USA.
McKinsey
Timothy A
TA
Newkirk
Scott
S
Huynh
Khai
K
Sucharov
Carmen C
CC
Bristow
Michael R
MR
D021581:Active Transport, Cell Nucleus; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D026161:MADS Domain Proteins / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008297:Male; D008875:Middle Aged; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D010766:Phosphorylation; D014157:Transcription Factors / Q000378:metabolism
D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D006655:Histone Deacetylases