Journal Article

δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

Hill, Joseph A, Bassel-Duby, Rhonda, Qi, Xiaoxia, Grueter, Chad E, Maier, Lars S, Lehmann, Lorenz H, Backs, Johannes, Neef, Stefan, Olson, Eric N, Richardson, James A, Kreusser, Michael M, Backs, Thea, Patrick, David M, Katus, Hugo A

2009

Overview

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 CaMKIIδ, the major CaMKII isoform expressed in the heart, we generated CaMKIIδ-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 CaMKIIδ-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 CaMKIIδ-null mice, underscoring the specificity of the CaMKIIδ signaling pathway for HDAC4 phosphorylation. We conclude that CaMKIIδ 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 CaMKIIδ as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Biological Sciences / Calcium - metabolism / calcium signaling / calcium-calmodulin-dependent protein kinase / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - chemistry / Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism / cardiac output / Cardiomegaly / Cardiomegaly - pathology / Exons / Heart / heart diseases / histone deacetylase / Histone Deacetylases - metabolism / Histones / Hypertrophy / Mice / Mice, Knockout / Models, Biological / Models, Genetic / Myocardial Infarction / Pathology / Phosphorylation / Polycystic kidney diseases / Protein Isoforms / Protein Kinase C - antagonists & inhibitors / Protein Kinase C - metabolism / Recombination, Genetic / Renovations / Signal Transduction