Abstract 17618: Casein Kinase 2-Dependent Phosphorylation of Histone Deacetylase 2 S394 Mediates Cardiac Hypertrophy
Cardiac hypertrophy is an adaptive response to various exogenous stresses including hypertension, valvular dysfunction and even myocardiac infarction, which is characterized by an enlargement of individual cardiomyocytes without increase in the cell population. Although initial response is a physiologic change, sustained stimuli lead to pathologic hypertrophy with many clinical features. We previously reported that activation of histone deacetylase (HDAC) 2, a class I HDAC, is required for the development of cardiac hypertrophy. However regulation mechanism of Hdac2 remains unclear. Neither expression level of Hdac2 nor the intracellular localization was altered in response to hypertrophic stimuli. However, phosphorylation of Hdac2 was greatly enhanced in cardiac hypertrophy, which was completely abolished by administration of casein kinase (CK) 2 inhibitors. By using diverse in vitro kinase assays, we demonstrated that Hdac2 S394 and S411 residues are responsible for the hypertrophy-induced phosphorylation. However, only phosphorylation of S394 was associated with the increase in the Hdac2 activation and with following hypertrophic phenotypes in the heart. By hypertrophic stimuli, CK2 was activated and translocated into the nucleus. Forced expression of CK2 activated Hdac2, while siCK2 abolished the activation as well as its phosphorylation. 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 isoproterenol-induced cardiac hypertrophy. αMHC-promoter-driven wild type-Hdac2 overexpressing transgenic mice showed the dramatic hypertrophy, whereas Hdac2 S394A-expressing transgenic did not show hypertrophic phenotypes. Heart was greatly enlarged in CK2-transgenic mice.These results suggest that phosphorylation of Hdac2 S394 by CK2 and subsequent activation of Hdac2 plays an important role in development of cardiac hypertrophy
- © 2010 by American Heart Association, Inc.