Calmodulin kinase II inhibition protects against structural heart disease

Abstract

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.

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

“…Aberrant Ca 2ϩ signaling has been implicated in the transmission of stress signals leading to pathological cardiac remodeling (4). Multiple Ca 2ϩ -dependent signaling molecules, including the Ca 2ϩ /calmodulindependent phosphatase calcineurin, protein kinase D (PKD) and Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) have been shown to transduce pathological Ca 2ϩ signals in the heart, and inhibitors directed against these enzymes sustain cardiac function in response to stress (5)(6)(7)(8)(9). However, the relative roles of these signal transducers and the extent to which their functions are distinct or redundant have not been fully elucidated.…”

“…CaMKII␦ expression and activity are up-regulated in structural heart disease (25,26), and transgenic overexpression of the nuclear splice variant CaMKII␦B (27) or the cytosolic splice variant CaMKII␦C (28) promotes cardiac hypertrophy. Conversely, inhibition of CaMKII activity with a peptide (AC3-I) diminishes pathological cardiac remodeling in response to stress (7). However, whether the involvement of CaMKII in heart disease reflects the actions of a specific isoform or multiple isoforms of the kinase remains to be determined.…”

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

“…Myocardial effects of K ATP channel current up-regulation are mirrored in many ways by inhibition of calcium/calmodulin-dependent protein kinase II (CaMKII), including shortened action potentials, improved resistance to cell death under metabolic stress, and normalized intracellular calcium homeostasis (32)(33)(34), suggesting a potential interaction between K ATP channels and CaMKII in a common calcium-related regulatory pathway. CaMKII is a multifunctional kinase, densely expressed in cardiomyocytes, that targets numerous proteins involved in excitation-contraction coupling and excitability to support short-term enhancement of cardiac performance, whereas persistent activation results in adverse cardiac remodeling and dysfunction (35)(36)(37)(38).…”

Vitamin A for the heart: progress for cardiac hypertrophy regression?

“…Also, the recently clinically introduced renin inhibitors (e.g., aliskiren) can block the RAAS at the very beginning of its signaling cascade; however, completely novel approaches to target additional stress pathways and thus the progression of cardiac hypertrophy and heart failure are urgently needed. In recent years, several new hypertrophic signaling pathways were found and further investigated (5,6,9), but only a few approaches were experimentally studied to inhibit the circulus vitiosus found in these cardiac diseases (6,12).…”