Calmodulin-dependent protein kinase II: linking heart failure and arrhythmias.

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.

journal_name

Circ Res

journal_title

Circulation research

authors

Swaminathan PD,Purohit A,Hund TJ,Anderson ME

doi

10.1161/CIRCRESAHA.111.243956

subject

Has Abstract

pub_date

2012-06-08 00:00:00

pages

1661-77

issue

12

eissn

0009-7330

issn

1524-4571

pii

110/12/1661

journal_volume

110

pub_type

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