CaMKII in myocardial hypertrophy and heart failure

Abstract

Many signals have risen and fallen in the tide of investigation into mechanisms of myocardial hypertrophy and heart failure (HF). In our opinion, the multifunctional Ca and calmodulin-dependent protein kinase II (CaMKII) has emerged as a molecule to watch, in part because a solid body of accumulated data essentially satisfy Koch's postulates, showing that the CaMKII pathway is a core mechanism for promoting myocardial hypertrophy and heart failure. Multiple groups have now confirmed the following: (1) that CaMKII activity is increased in hypertrophied and failing myocardium from animal models and patients; (2) CaMKII overexpression causes myocardial hypertrophy and HF and (3) CaMKII inhibition (by drugs, inhibitory peptides and gene deletion) improves myocardial hypertrophy and HF. Patients with myocardial disease die in equal proportion from HF and arrhythmias, and a major therapeutic obstacle is that drugs designed to enhance myocardial contraction promote arrhythmias. In contrast, inhibiting the CaMKII pathway appears to reduce arrhythmias and improve myocardial responses to pathological stimuli. This brief paper will introduce the molecular physiology of CaMKII and discuss the impact of CaMKII on ion channels, Ca handling proteins and transcription in myocardium. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure".

Fig. 1

CaMKII structural domains and regulation. CaMKII monomers consist of an N terminal catalytic domain and a C terminal association domain that bound a regulatory domain (top). The association domains (maroon circles) are required for assembly of the CaMKII monomers into the holoenzyme (middle panels). Under resting conditions the catalytic domain is constrained by the regulatory domain (left middle and bottom panels). After intracellular Ca²⁺ rises and complexes with calmodulin (CaM) the Ca²⁺/CaM binds to the C terminal portion of the CaMKII regulatory domain (mid portion of the top, middle and bottom panels) to prevent autoinhibition of the regulatory domain on the catalytic domain, activating CaMKII. With sustained Ca²⁺/CaM or increased oxidation, CaMKII transitions into a Ca²⁺/CaM-autonomous active enzyme after autophosphorylation (at Thr 287) or oxidation (at Met281/282) of amino acids in the regulatory domain.

Fig. 2

The relationship of CaMKII to upstream activators and target proteins in cardiomyocytes. CaMKII is present in cardiomyocytes where it is activated by Ca/CaM, ROS and Epac. Activation of β-adrenergic receptors (β-AR) can activate CaMKII by way of adenylyl cyclase (AC) that leads to increased Epac and increased protein kinase A (PKA). Other G-protein coupled receptor (GPCR) agonists (angiotensin II, AngII; norepinephrine, NE and endothelin-1, ET1) can increase cytoplasmic ROS by activating NAPDH oxidase, and increase Ca release from inositol triphosphate receptors (IP₃R) in the nuclear envelope that activate nuclear CaMKII to increase prehypertrophic signaling by type II histone deacetylase (HDAC) derepression of myocyte enhancer factor 2 (MEF2). Activated CaMKIIδ (the predominant myocardial isoform) induces stimulatory actions by phosphorylating major Ca homeostatic proteins to increase L-type Ca current (I_Ca), phospholamban (PLB) to increase cytosolic Ca uptake by the sarcoplasmic reticulum (SR), and ryanodine receptor (RyR) to increase SR Ca release, which activates inward Na current due to the Na/Ca exchanger (NCX). CaMKII catalyzes phosphorylation of voltage-gated ion channels responsible for Na current (I_Na), transient outward K current (I_to) and inward rectifier K current (I_K1).