Identification and Expression of δ-Isoforms of the Multifunctional Ca ²⁺ /Calmodulin-Dependent Protein Kinase in Failing and Nonfailing Human Myocardium

Abstract

Abstract-Despite its importance for the regulation of heart function, little is known about the isoform expression of the multifunctional Ca 2ϩ /calmodulin-dependent protein kinase (CaMKII) in human myocardium. In this study, we investigated the spectrum of CaMKII isoforms ␦ 2 , ␦ 3 , ␦ 4 , ␦ 8 , and ␦ 9 in human striated muscle tissue. Isoform ␦ 3 is characteristically expressed in cardiac muscle. In skeletal muscle, specific expression of a new isoform termed ␦ 11 is demonstrated. Complete sequencing of human ␦ 2 cDNA, representing all common features of the investigated CaMKII subclass, revealed its high homology to the corresponding rat cDNA. Comparative semiquantitative reverse transcription-polymerase chain reaction analyses from left ventricular tissues of normal hearts and from patients suffering from dilated cardiomyopathy showed a significant increase in transcript levels of isoform ␦ 3 relative to the expression of glyceraldehyde-3-phosphate dehydrogenase in diseased hearts (101.6Ϯ11.0% versus 64.9Ϯ9.9% in the nonfailing group; PϽ0.05, nϭ6). Transcript levels of the other investigated cardiac CaMKII isoforms remained unchanged. At the protein level, by using a subclass-specific antibody, we observed a similar increase of a ␦-CaMKII-specific signal (7.2Ϯ1.0 versus 3.8Ϯ0.7 optical density units in the nonfailing group; PϽ0.05, nϭ4 through 6). The diseased state of the failing hearts was confirmed by a significant increase in transcript levels for atrial natriuretic peptide (292.9Ϯ76.4% versus 40.1Ϯ3.2% in the nonfailing group; PϽ0.05, nϭ3 through 6). Our data characterize for the first time the ␦-CaMKII isoform expression pattern in human hearts and demonstrate changes in this expression pattern in heart failure. (Circ Res. 1999;84:713-721.)

Human cardiomyocyte calcium handling and transverse tubules in mid‐stage of post‐myocardial‐infarction heart failure

“…The reduced CaMKII phosphorylation in mid‐phase stage HF patients in the present study is not easy to reconcile with earlier studies from both experimental animal models (reviewed by, e.g. Maier and Bers27) and explanted end‐stage human hearts showing augmented levels and activity of CaMKII 28, 29. However, more recent reports indicate controversies in terms of the activity of CaMKII in HF; data from explanted end‐stage failing human hearts show an important role of increased CaMKII activity measured by significantly increased RyR phosphorylation on the Ser‐2814 site,30 but importantly, this study did on the contrary not find increased levels of CaMKII phosphorylation on the RyR in severe aortic stenosis patients with compensated hypertrophy, indicating that CaMKII is not activated at earlier stages of HF in these patients 30.…”

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

“…The results of this study demonstrate that CaMKII␦, the major CaMKII isoform in the heart (25), is a critical component of the signaling pathways through which pressure overload drives pathological cardiac remodeling (Fig. 7).…”

“…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).…”

Blunderbuss to Mickey Mouse

“…It also has increased endogenous CaMKII activity. Important to our understanding of this model's value is the fact that CaMKII is associated with cardiomyopathy of diverse causes in human subjects, 24 as well as in animal models. 25,26 Also important is the central role of CaMKII as a "multifunctional kinase" 27 that induces change at the level of nucleus, cytoskeleton, and membrane.…”