Molecular Cardiology Casein Kinase-2 1 Induces Hypertrophic Response by Phosphorylation of Histone Deacetylase 2 S394 and its Activation in the Heart

Background—Cardiac hypertrophy is characterized by transcriptional reprogramming of fetal gene expression, and histone deacetylases (HDACs) are tightly linked to the regulation of those genes. We previously demonstrated that activation of HDAC2, 1 of the class I HDACs, mediates hypertrophy. Here, we show that casein kinase-2␣1 (CK2␣1)– dependent phosphorylation of HDAC2 S394 is required for the development of cardiac hypertrophy. Methods and Results—Hypertrophic stimuli phosphorylated HDAC2 S394, which was necessary for its enzymatic activation, and therefore the development of hypertrophic phenotypes in rat neonatal cardiomyocytes or in isoproterenol-administered mice hearts. 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 patients with hypertrophic cardiomyopathy. Hypertrophy-induced phosphorylation of HDAC2 S394 and its enzymatic activity were completely blocked either by CK2 blockers or by CK2␣1 short interfering RNA. Hypertrophic stimuli led CK2␣1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and isoproterenol-administered mice. CK2␣1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2␣1 caused hypertrophy in cardiomyocytes, whereas chemical inhibitors of both CK2 and HDAC as well as HDAC2 S394A blunted it. Hypertrophy in CK2␣1-transgenic mice was exaggerated by crossing these mice with wild-type-HDAC2-overexpressing mice. By contrast, however, it was blocked when CK2␣1-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. Key Words: hypertrophy Ⅲ casein kinase 2 Ⅲ histone deacetylase 2 S394 Ⅲ phosphorylation Ⅲ transgenic mice C ardiac hypertrophy, an increase in the size of cardiomyo-cytes, is often caused by diverse pathological conditions such as myocardial infarction, hypertension, aortic stenosis, and valvular dysfunction. Although cardiac hypertrophy itself is an initial adaptive process, uncorrected continuous stimuli often lead the heart to heart failure. Because heart failure is a main cause of human mortality, many researchers are eager to develop interventions to reverse cardiac hypertrophy or to prevent the transition to congestive heart failure. Posttranslational modifications of histones are closely involved in diverse biological processes through the regulation of transcription of downstream target genes. 1,2 Among these modifications, the acetylation status of the chromatin mediates the epigenetic regulation of gene expression. Two opposing groups of enzymes, histone acetyltransferase and histone deacetylases (HDACs), regulate the acetylation of histone. …