title: The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload.
abstract: Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads to pathological cardiac hypertrophy and remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transduction of calcium signals in the heart, but the specific isoforms of CaMKII that mediate pathological cardiac signaling have not been fully defined. To investigate the potential involvement in heart disease of CaMKIIdelta, the major CaMKII isoform expressed in the heart, we generated CaMKIIdelta-null mice. These mice are viable and display no overt abnormalities in cardiac structure or function in the absence of stress. However, pathological cardiac hypertrophy and remodeling are attenuated in response to pressure overload in these animals. Cardiac extracts from CaMKIIdelta-null mice showed diminished kinase activity toward histone deacetylase 4 (HDAC4), a substrate of stress-responsive protein kinases and suppressor of stress-dependent cardiac remodeling. In contrast, phosphorylation of the closely related HDAC5 was unaffected in hearts of CaMKIIdelta-null mice, underscoring the specificity of the CaMKIIdelta signaling pathway for HDAC4 phosphorylation. We conclude that CaMKIIdelta functions as an important transducer of stress stimuli involved in pathological cardiac remodeling in vivo, which is mediated, at least in part, by the phosphorylation of HDAC4. These findings point to CaMKIIdelta as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload.
authors.affiliation: Department of Internal Medicine III University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Backs
authors.forename: Thea
authors.initials: T
authors.lastname: Backs
authors.forename: Stefan
authors.initials: S
authors.lastname: Neef
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kreusser
authors.forename: Lorenz H
authors.initials: LH
authors.lastname: Lehmann
authors.forename: David M
authors.initials: DM
authors.lastname: Patrick
authors.forename: Chad E
authors.initials: CE
authors.lastname: Grueter
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qi
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006332:Cardiomegaly / Q000473:pathology*; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008957:Models, Genetic; D009203:Myocardial Infarction; D010766:Phosphorylation; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction
chemical_list: D020033:Protein Isoforms; C089212:protein kinase D; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D002118:Calcium