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Article
Nature Medicine 11, 409 - 417 (2005)
Published online: 27 March 2005 | doi:10.1038/nm1215
Calmodulin kinase II inhibition protects against structural heart disease
Rong 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 Anderson1,3
Abstract
-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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