Abstract 12058: Expression and Activity of Histone Deacetylases are Increased in Hypoplastic Left Heart Syndrome
Background: Hypoplastic Left Heart Syndrome (HLHS) is the most common form of severe congenital heart disease and is characterized by underdevelopment of all left-sided heart structures. Failure of the systemic right ventricle (RV) is a common cause of death and indication for transplant and is without proven therapy. Histone deacetylases (HDACs) are enzymes that deacetylate lysine residues on histone and non-histone proteins and have been linked to many different processes in the failing heart. The purpose of this study was to investigate the role of HDACs in HLHS. We hypothesize that HDACs play a role in mediating pathologic adaptation of the systemic RV and that modulation of HDAC activity, given the distal site of action in hypertrophic signaling pathways, could have unique therapeutic potential.
Methods: RNA, protein and whole tissue extracts were isolated from the RV of infants and children with HLHS and from non-failing (NF) pediatric donor RV. RTqPCR for HDAC isoforms and Western blots using isoform specific antibodies for Class I and II HDACs were performed. Enzymatic activities of class I, IIa, and IIb HDACs were measured using class-selective, fluorogenic substrates based on acetylated lysine.
Results: There was increased mRNA expression (n=8 NF and 8 HLHS) of class IIa (HDAC-4,5 and 9) and class IIb (HDAC-6) HDAC isoforms in the RV of children with HLHS. Protein expression (n=6 NF and 5 HLHS) of HDAC-1 (class I HDAC) and HDAC-5 were significantly increased in HLHS RV (Figure). Although there was a trend towards increased expression of HDAC-6, this was not significant. There was increased activity (n=6 NF and 6 HLHS) of HDACs class I, IIa and IIb in HLHS RV compared to NF-RV.
Conclusion: HDAC mRNA, protein expression and activity are increased in the systemic RV of children with HLHS. Modulation of HDAC activity, given the distal site of action in the hypertrophic signaling pathway, could have unique therapeutic potential in RV failure in HLHS.
- © 2012 by American Heart Association, Inc.