Abstract
Background
Histone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac diseases. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle (SV) heart disease of right ventricular morphology, as well as in a rodent model of right ventricular hypertrophy (RVH).
Methods
Homogenates of right ventricle (RV) explants from non-failing controls and children born with a SV were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day-old rat pups were placed in hypoxic conditions, and echocardiographic analysis, gene expression, HDAC catalytic activity, and isoform expression studies of the RV were performed.
Results
Class I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in the hearts of children born with a SV. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression, elevated class I and class IIb HDAC catalytic activity, and protein expression in the RV compared with those in the control.
Conclusions
These data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. Although further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for preclinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies.
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This work was supported by NIH R21 HL113846 to S.D.M., T.A.M and C.S.L. S.D.M. was also supported by NIH (R01 HL126928), the Addison Scott Memorial Fund, the Boedecker Foundation, the Nair Family, and the Millisor Chair in Pediatric Heart Disease. T.A.M. was also supported by NIH (HL116848, HL127240 and AG043822) and the American Heart Association (GIA14510001 and 16SFRN31400013). W.W.B was supported by the University of Colorado-Denver Pharmacology Program NIH T32 Training Grant (GM007635).
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Blakeslee, W., Demos-Davies, K., Lemon, D. et al. Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy. Pediatr Res 82, 642–649 (2017). https://doi.org/10.1038/pr.2017.126
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DOI: https://doi.org/10.1038/pr.2017.126
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