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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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Backs J,Backs T,Neef S,Kreusser MM,Lehmann LH,Patrick DM,Grueter CE,Qi X,Richardson JA,Hill JA,Katus HA,Bassel-Duby R,Maier LS,Olson EN

doi

10.1073/pnas.0813013106

subject

Has Abstract

pub_date

2009-02-17 00:00:00

pages

2342-7

issue

eissn

0027-8424

issn

1091-6490

pii

0813013106

journal_volume

106

pub_type

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