Inhibition of cardiac CaMKII to cure heart failure: step by step towards translation?

During the past decade, calcium/calmodulin-dependent protein kinase II (CaMKII) has emerged as a central culprit in the development of cardiac arrhythmia and heart failure.This has been supported by a plethora of studies using transgenic mouse models and pharmacological CaMKII inhibitors and peptides.However, the final proof that CaMKII inhibition improves dysfunction of a failing heart is still pending.In this issue, Kreusser et al. [19] demonstrated that knockdown of the two key cardiac CaMKII isoforms after the onset of hemodynamic stress succeeds to reverse maladaptive cardiac remodeling processes.Their study is an important step in translating CaMKII inhibition from bench to bedside for heart failure therapy.CaMKII is a multifunctional protein kinase that plays a pivotal role in cardiac (patho) physiology [27,40].It represents a nodal point in the regulation of intracellular Ca 2? handling, ion channels and gene transcription.As the description ''multifunctional'' and ''nodal point'' implies, this kinase is intertwined into a complex cellular signaling network and thus tricky to manipulate therapeutically: CaMKII activity is regulated by posttranslational modifications that allow maintenance of kinase activity independently of Ca 2? /calmodulin-binding.Amongst those autophosphorylation [16,26,45], oxidation [2, 7, 13, 32, 45], O-linked N-acetylglucosamination [9] and S-nitrosylation [8, 12] have been described to date.CaMKII has various cellular targets in Ca 2? homeostasis some of which are the ryanodine receptor [26,34,39,41], phospholamban [5,18] and cardiac myosin-binding protein C [37].Furthermore, CaMKII impacts on L-type Ca 2? channel (LTCC) currents and LTCC expression [40], on expression of the Na ?/Ca 2? exchanger [10,23] and the sarcoplasmic reticulum Ca 2? ATPase 2a (SERCA2a) [5,23,42] as well as on gene transcription via the regulation of calcineurin and class II histone deacetylase isoforms [3,24].CaMKII is ubiquitously expressed, with a and b as predominant isoforms in the brain, where they are important for neuronal function and cognitive memory.CaMKIIc and d are the key isoforms expressed in the heart.Particular attention has been paid to two CaMKIId splice variants in the heart, CaMKIId B and CaMKIId C .CaMKIId B has an 11 amino acid nuclear localization sequence that is absent in CaMKIId C .Studies performed in splice-variant-specific knockout mouse models have attributed a protective functional role to CaMKIId B .Thus, cellular localization seems to participate in CaMKII isoform-specific pathophysiological roles [4,5,28,44].Despite of the physiological importance of CaMKII, for e.g,.excitation-contraction coupling, isoproterenol-induced