Circulation Research. 2003;92:912-919
Published online before print April 3, 2003, doi: 10.1161/01.RES.0000069686.31472.C5
Published online before print April 3, 2003, doi: 10.1161/01.RES.0000069686.31472.C5
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© 2003 American Heart Association, Inc.
Integrative Physiology |
The 
C Isoform of CaMKII Is Activated in Cardiac Hypertrophy and Induces Dilated Cardiomyopathy and Heart Failure
From the Departments of Pharmacology (T.Z., S.M., J.H.B.) and Medicine (N.D.D., J.R.), University of California, San Diego, La Jolla, Calif; and the Department of Physiology (L.S.M., D.M.B.), Loyola University, Chicago, Ill. Present address for L.S.M. is the Department of Cardiology, Georg-August Universitaet Goettingen, Germany.
Correspondence to Joan Heller Brown, Department of Pharmacology, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0636. E-mail jhbrown{at}ucsd.edu
Recent studies have demonstrated that transgenic (TG) expression of either Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) or CaMKII
B, both of which localize to the nucleus, induces cardiac hypertrophy. However, CaMKIV is not present in heart, and cardiomyocytes express not only the nuclear CaMKIIB but also a cytoplasmic isoform, CaMKIIC. In the present study, we demonstrate that expression of the C 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 C isoform of CaMKII can lead to phosphorylation of Ca2+ regulatory proteins and induce hypertrophy, we generated TG mice that expressed the C 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 CaMKIIC can mediate phosphorylation of Ca2+ regulatory proteins in vivo and provide evidence for the involvement of CaMKIIC activation in the pathogenesis of dilated cardiomyopathy and heart failure.
Key Words: Ca2+/calmodulin-dependent protein kinase II • transgenic mice • dilated cardiomyopathy • heart failure
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