Calmodulin-Dependent Protein Kinase II: Linking Heart Failure and Arrhythmias

Author:

Swaminathan Paari Dominic1,Purohit Anil1,Hund Thomas J.1,Anderson Mark E1

Affiliation:

1. From the Division of Cardiovascular Medicine (P.D.S., A.P., M.E.A.), Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA; Department of Biomedical Engineering (T.J.H.), The Ohio State University, Columbus, OH; Department of Molecular Physiology and Biophysics (M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA.

Abstract

Understanding relationships between heart failure and arrhythmias, important causes of suffering and sudden death, remains an unmet goal for biomedical researchers and physicians. Evidence assembled over the past decade supports a view that activation of the multifunctional Ca 2+ and calmodulin-dependent protein kinase II (CaMKII) favors myocardial dysfunction and cell membrane electrical instability. CaMKII activation follows increases in intracellular Ca 2+ or oxidation, upstream signals with the capacity to transition CaMKII into a Ca 2+ and calmodulin-independent constitutively active enzyme. Constitutively active CaMKII appears poised to participate in disease pathways by catalyzing the phosphorylation of classes of protein targets important for excitation–contraction coupling and cell survival, including ion channels and Ca 2+ homeostatic proteins, and transcription factors that drive hypertrophic and inflammatory gene expression. This rich diversity of downstream targets helps to explain the potential for CaMKII to simultaneously affect mechanical and electrical properties of heart muscle cells. Proof-of-concept studies from a growing number of investigators show that CaMKII inhibition is beneficial for improving myocardial performance and for reducing arrhythmias. We review the molecular physiology of CaMKII and discuss CaMKII actions at key cellular targets and results of animal models of myocardial hypertrophy, dysfunction, and arrhythmias that suggest CaMKII inhibition may benefit myocardial function while reducing arrhythmias.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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