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.

Assist devices fail to reverse patterns of fetal gene expression despite beta-blockers.

BACKGROUND: Heart failure is associated with reversal to a fetal gene expression pattern of contractile and metabolic genes. Substantial recovery of ventricular function with assist devices is rare. Our goal was to evaluate the effects of assist devices on fetal gene expression and hypoxia inducible factor-1 alpha (HIF-1 alpha), a transcriptional factor in hypoxic signaling. METHODS: Human heart tissue was obtained from the left ventricular apex at the time of assist device implantation and again from the left ventricular free wall during cardiac transplantation. Non-failing tissue was obtained from unused hearts from human donors. Gene expression was measured with the Affymetrix 133 plus 2 Array. HIF-1 alpha was measured by Western blotting with commercially available antibodies. RESULTS: Heart failure was associated with a decrease in alpha-myosin heavy chain and sarcoplasmic reticulum-Ca(2+) adenosine triphosphatase messenger RNA expression along with an increase in skeletal tropomyosin. This pattern persisted after assist device therapy. Heart failure was also associated with abnormalities in regulatory metabolic genes including glucose transporter 1 (GLUT1). These patterns also persisted after assist device therapy despite a reduction in atrial natriuretic peptide expression and normalization of HIF-1 alpha. CONCLUSIONS: Failure of assist devices to produce sustained recovery of myocardial contractile function may be due in part to persistent fetal transcriptional patterns of contractile and metabolic genes.