Abstract P187: Casein Kinase 2/Histone Deacetylase 2/Krúppel-like Factor 4 Is a Novel Axis of Development of Cardiac Hypertrophy
Background. Cardiac hypertrophy is characterized by transcriptional reprogramming of fetal gene expression, and histone modifiers are tightly linked to the regulation of those genes. We previously reported that activation of histone deacetylase (HDAC) 2, one of the class I HDACs, mediates hypertrophy. Here we suggest that disinhibiting of kruppel-like factor 4 (Klf4) by casein kinase-2α1 (CK2α1)-dependent phosphorylation of HDAC2 S394 develop the cardiac hypertrophy.
Methods and Results. Hypertrophic stimuli phosphorylated Hdac2 S394, which was necessary for its enzymatic activation and thereby for the development of hypertrophic phenotypes. Transgenic mice overexpressing Hdac2-wild type exhibited cardiac hypertrophy, whereas those expressing phosphorylation-resistant Hdac2 S394A did not. Compared with that in age-matched normal human hearts, phosphorylation of Hdac2 S394 was dramatically increased in hypertrophic cardiomyopathy patients. Hypertrophy-induced phosphorylation of Hdac2 S394 and its enzymatic activity were completely blocked either by CK2-blockers or by CK2a1 siRNA. Hypertrophic stimuli led CK2α1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and in isoproterenol-administered mice. However, by utilizing KLF4-binding element-disrupted Nppa promoter, treatment with either TBB or TBCA failed to reduce the mutant promoter activity. These results emphasized that CK2α1-induced hypertrophic events are dependent on both Hdac2 and KLF4. CK2α1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2α1 caused hypertrophy in cardiomyocytes, whereas its chemical inhibitors as well as Hdac2 S394A blunted it. Hypertrophy in CK2α1-transgenic mice was exaggerated by crossing these mice with Hdac2-transgenic mice. By contrast, however, it was blocked when CK2α1-transgenic mice were crossed with Hdac2 S394A-transgenic mice.
Conclusions. We have demonstrated a novel mechanism in the development of cardiac hypertrophy by which CK2 activates HDAC2 via phosphorylating HDAC2 S394 and consequence down-regulation of KLF4.
- © 2011 by American Heart Association, Inc.