Role of Ca2+/calmodulin-dependent protein kinase II in cardiac hypertrophy and heart failure

Ca2+/calmodulin-dependent protein kinase II (CaMKII), a critical transducer of Ca2+ signaling, is a multifunctional protein kinase which can phosphorylate a wide range of substrates and regulate numerous cellular functions. The delta isoforms of CaMKII predominate in the heart and two splice variants of CaMKIIdelta, delta(B) and delta(C), have been demonstrated to be present in the adult mammalian myocardium. The delta(B) isoform contains a nuclear localization signal (NLS) that is absent from delta(C), and consequently, the two isoforms have different subcellular localization. Recent work from our laboratory and others has implicated CaMKII in the development of cardiac hypertrophy and heart failure. The specific roles of these CaMKII isoforms in regulating cardiac function appear to be determined by their subcellular localization. The nuclear delta(B) isoform plays a key role in hypertrophic gene expression, whereas the cytoplasmic delta(C) isoform can affect excitation-contraction (E-C) coupling through phosphorylation of Ca2+ regulatory proteins and may also transduce signals leading to apoptosis. In addition, the nuclear delta(B) and the cytoplasmic delta(C) isoforms of CaMKII are differentially regulated in pressure overload-induced cardiac hypertrophy. This review focuses on evidence that CaMKII plays an essential role in transcriptional activation associated with cardiac hypertrophy, as well as the aberrant Ca2+ handling and apoptosis that may contribute to heart failure. The hypothesis that CaMKII isoform selective activation, localization and substrate phosphorylation lead to specificity in the resultant signaling pathways is discussed. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.