CaMKII and a failing strategy for growth in heart

Abstract

Patients with systolic left ventricular dysfunction die progressively from congestive heart failure or die suddenly from cardiac arrhythmias. Myocardial hypertrophy is an early event in most forms of heart failure, but the majority of patients with myocardial hypertrophy do not develop heart failure. Developing improved therapies for targeting the cell signaling pathways that enable this deadly transition from early myocardial insult to heart failure and sudden death is a key goal for improving public health. In this issue of the JCI, Ling and colleagues provide new evidence that activation of the multifunctional Ca(2+)/calmodulin-dependent kinase IIdelta is a decisive step on the path to heart failure in mice (see the related article beginning on page 1230).

Figure 1. CaMKII activation is initiated by Ca²⁺/CaM, sustained by autophosphorylation and oxidation, and leads to downstream cellular events important for the development of heart failure.

(A) Ca²⁺/CaM–activated CaMKII transitions to Ca²⁺/CaM–autonomous activity by exposure to ROS or through autophosphorylation. Excessive CaMKII activity triggers diverse, maladaptive cellular events important for the transition from early myocardial stress to late-stage myocardial diseases of heart failure, arrhythmias, and sudden death. (B) Top: The CaMKII holoenzyme and a single CaMKII subunit. The regulatory domain consists of an autoinhibitory region (AI) and a calmodulin-binding region (CaM-B). Bottom: CaMKII becomes constitutively active by autophosphorylation (P) and/or oxidation (O).