The cardiac-specific nuclear delta(B) isoform of Ca2+/calmodulin-dependent protein kinase II induces hypertrophy and dilated cardiomyopathy associated with increased protein phosphatase 2A activity.
The delta isoform of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) predominates in the heart. To investigate the role of CaMKII in cardiac function, we made transgenic (TG) mice that express the nuclear delta(B) isoform of CaMKII. The expressed CaMKIIdelta(B) transgene was restricted to the myocardium and highly concentrated in the nucleus. Cardiac hypertrophy was evidenced by an increased left ventricle to body weight ratio and up-regulation of embryonic and contractile protein genes including atrial natriuretic factor, beta-myosin heavy chain, and alpha-skeletal actin. Echocardiography revealed ventricular dilation and decreased cardiac function, which was also observed in hemodynamic measurements from CaMKIIdelta(B) TG mice. Surprisingly, phosphorylation of phospholamban at both Thr(17) and Ser(16) was significantly decreased in the basal state as well as upon adrenergic stimulation. This was associated with diminished sarcoplasmic reticulum Ca(2+) uptake in vitro and altered relaxation properties in vivo. The activity and expression of protein phosphatase 2A were both found to be increased in CaMKII TG mice, and immunoprecipitation studies indicated that protein phosphatase 2A directly associates with CaMKII. Our findings are the first to demonstrate that CaMKII can induce hypertrophy and dilation in vivo and indicate that compensatory increases in phosphatase activity contribute to the resultant phenotype.
Zhang
Tong
T
Department of Pharmacology and Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Johnson
Eric N
EN
Gu
Yusu
Y
Morissette
Michael R
MR
Sah
Valerie P
VP
Gigena
Marisa S
MS
Belke
Darrell D
DD
Dillmann
Wolfgang H
WH
Rogers
Terry B
TB
Schulman
Howard
H
Ross
John
J
Brown
Joan Heller
JH
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006332:Cardiomegaly / Q000473:pathology / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000473:pathology / Q000503:physiopathology*; D004280:Dobutamine / Q000494:pharmacology; D004452:Echocardiography; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004280:Dobutamine; D007527:Isoenzymes; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000099211:Phospholamban