Calmodulin kinase II inhibition protects against structural heart disease.
Beta-adrenergic receptor (betaAR) stimulation increases cytosolic Ca(2+) to physiologically augment cardiac contraction, whereas excessive betaAR activation causes adverse cardiac remodeling, including myocardial hypertrophy, dilation and dysfunction, in individuals with myocardial infarction. The Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a recently identified downstream element of the betaAR-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 betaAR signaling in vivo. Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive betaAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and betaAR-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 betaAR signaling.
Zhang
Rong
R
Department of Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, Tennessee 37232-6300, USA.
Khoo
Michelle S C
MS
Wu
Yuejin
Y
Yang
Yingbo
Y
Grueter
Chad E
CE
Ni
Gemin
G
Price
Edward E
EE
Thiel
William
W
Guatimosim
Silvia
S
Song
Long-Sheng
LS
Madu
Ernest C
EC
Shah
Anisha N
AN
Vishnivetskaya
Tatiana A
TA
Atkinson
James B
JB
Gurevich
Vsevolod V
VV
Salama
Guy
G
Lederer
W J
WJ
Colbran
Roger J
RJ
Anderson
Mark E
ME
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D002303:Cardiac Output, Low; D006332:Cardiomegaly; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D020257:Ventricular Remodeling
D000319:Adrenergic beta-Antagonists; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium