Nature Medicine
11, 409 - 417 (2005)
Published online: 27 March 2005; | doi:10.1038/nm1215
Calmodulin kinase II inhibition protects against structural heart diseaseRong Zhang1, 8, Michelle S C Khoo1, 8, Yuejin Wu1, 8, Yingbo Yang1, 8, Chad E Grueter2, Gemin Ni1, Edward E Price Jr.2, William Thiel3, Silvia Guatimosim4, 5, Long-Sheng Song4, Ernest C Madu1, Anisha N Shah6, Tatiana A Vishnivetskaya3, James B Atkinson7, Vsevolod V Gurevich3, Guy Salama6, W J Lederer4, Roger J Colbran2
& Mark E Anderson1, 31
Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, Tennessee 37232-6300, USA. 2
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, Tennessee 37232-6300, USA. 3
Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, Tennessee 37232-6300, USA. 4
Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21021, USA. 5
Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil. 6
Department of Cell Biology, University of Pittsburgh School of Medicine, S362 Biomedical Science Tower, 3500 Terrace Street, Pittsburgh, Pennsylvania 15261, USA. 7
Department of Pathology, Vanderbilt University School of Medicine, Medical Center North C3320, Nashville, Tennessee 37232-2561, USA. 8
These authors contributed equally to this work.
Correspondence should be addressed to Mark E Anderson mark.anderson@vanderbilt.edu -Adrenergic receptor (AR) stimulation increases cytosolic Ca2+ to physiologically augment cardiac contraction, whereas excessive AR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca2+-calmodulin−dependent protein kinase II (CaMKII) is a recently identified downstream element of the AR-initiated signaling cascade that is linked to pathological myocardial remodeling and to regulation of key proteins involved in cardiac excitation-contraction coupling. We developed a genetic mouse model of cardiac CaMKII inhibition to test the role of CaMKII in AR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive AR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and AR-stimulated physiological increases in cardiac function. These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to AR signaling.
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