Recent studies have demonstrated that transgenic (TG) expression of either Ca2+/
calmodulin-dependent protein kinase IV (CaMKIV) or CaMKIIdeltaB, both of which localize to the nucleus, induces
cardiac hypertrophy. However, CaMKIV is not present in heart, and cardiomyocytes express not only the nuclear CaMKIIdeltaB but also a cytoplasmic
isoform, CaMKIIdeltaC. In the present study, we demonstrate that expression of the deltaC
isoform of
CaMKII is selectively increased and its phosphorylation elevated as early
as 2 days and continuously for up to 7 days after pressure overload. To determine whether enhanced activity of this cytoplasmic deltaC
isoform of
CaMKII can lead to phosphorylation of Ca2+ regulatory
proteins and induce
hypertrophy, we generated TG mice that expressed the deltaC
isoform of
CaMKII. Immunocytochemical staining demonstrated that the expressed transgene is confined to the cytoplasm of cardiomyocytes isolated from these mice. These mice develop a
dilated cardiomyopathy with up to a 65% decrease in fractional shortening and die prematurely. Isolated myocytes are enlarged and exhibit reduced contractility and altered Ca2+ handling. Phosphorylation of the
ryanodine receptor (RyR) at a
CaMKII site is increased even before development of
heart failure, and
CaMKII is found associated with the RyR in immunoprecipitates from the
CaMKII TG mice. Phosphorylation of
phospholamban is also increased specifically at the
CaMKII but not at the PKA phosphorylation site. These findings are the first to demonstrate that CaMKIIdeltaC can mediate phosphorylation of Ca2+ regulatory
proteins in vivo and provide evidence for the involvement of CaMKIIdeltaC activation in the pathogenesis of
dilated cardiomyopathy and
heart failure.