Background : Cardiac hypertrophy is a dynamic response to various exogenous stresses including hypertension, valvular dysfunction and even myocardial infarction, which is characterized by an enlargement of individual cardiomyocytes without increase in the cell number. Although initial response is a physiologic adaptation, sustained stimuli lead to pathologic hypertrophy in many clinical features.
Methods and Results : We previously reported that activation of histone deacetylase (HDAC) 2, a class I Hdac, is a key protein of development of cardiac hypertrophy. However regulation mechanism of HDAC2 remains unclear. The expression level of Hdac2 was not increased. Recombinant GST-Hdac2 was phosphorylated in vitro by applying heart lysates obtained from isoproterenol-treated mice, which was completely abolished by simultaneous treatment with a casein kinase (CK) 2 inhibitors. Hypertrophic stimuli activated CK2, and subcellular localization of CK2 was enriched in the nucleus. CK2 inhibitor not only blocked hypertrophic stimuli-induced activation of Hdac2 but blunted Nppa-luc promoter activity which was transactivated by phenylephrine. In vivo administration of CK2 inhibitor blocked isoprotereanol-induced cardiac hypertrophy. According to in vitro kinase assay, Hdac2 S394 was phosphorylated by CK2 and phosphorylation-resistant mutant by of substitution S394 as A394, did not show full activity when compared with wild type of Hdac2. CK2-overexpressing transgenic mice elicited enhancement of response to exogenous hypertrophic stimuli.
Conclusions : These results suggest that phosphorylation of Hdac2 S394 by CK2 and subsequent activation of Hdac2 plays an important role in development of cardiac hypertrophy.