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 Special Issue”.

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

“…Two recent studies indicated NO-mediated regulation of CaMKII also in the heart (46,47), where CaMKII is known to have crucial pathological functions (13). However, in this case, CaMKII activation by NO did not appear to be through direct S-nitrosylation, as CaMKII activation (and the downstream functions) was instead dependent on PKG (47), which is activated by cGMP after NO-induced guanylyl cyclase activation (17)(18)(19).…”

“…Several ways to generate CaMKII autonomy have been prominently described over three decades, and include several very recent additions: Thr-286 autophosphorylation (8,9), T-site-mediated GluN2B binding (10), Met-281/282 oxidation (11), and Ser-279 glycosylation (12) (Fig. 1), the latter two for the CaMKIIó isoform that is dominant in the heart (13). In all cases, an initial Ca 2ϩ /CaMstimulation is required to induce the CaMKII autonomy, which then persists when the Ca 2ϩ stimulus has subsided and Ca 2ϩ / CaM has dissociated.…”

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

“…First, CaMKII is a vital regulator of cardiac excitation-contraction coupling and, thus, cardiac energy consumption (35)(36)(37). Second, CaMKII activation underlies increased cardiac performance during heart rate acceleration (38,50), an established trigger of K ATP channel opening (23,24).…”

“…On the other hand, chronic CaMKII activation, as occurs in disease states such as heart failure (35,37,38), would prohibit resetting of the normal baseline K ATP channel surface density. This would blunt the protective shortening of action potentials under repeated acute stress, thereby predisposing myocytes to worsened energetic insult and injury that would promote disease progression.…”

“…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). Indeed, inhibition of CaMKII has been shown to increase cardioprotective K ATP channel surface presence and current density (29).…”