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