Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
J Mol Cell Cardiol. 2011 Oct;51(4):468-73. doi: 10.1016/j.yjmcc.2011.01.012. Epub 2011 Jan 27.
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".
在对心肌肥厚和心力衰竭（HF）机制的研究中，许多信号如潮水般起起落落。在我们看来，多功能 Ca 和钙调蛋白依赖性蛋白激酶 II（CaMKII）已经成为一个值得关注的分子，部分原因是大量积累的数据基本上满足了 Koch 的假设，表明 CaMKII 通路是促进心肌肥厚和心力衰竭的核心机制。多个小组已经证实：（1）在动物模型和患者的肥厚和衰竭心肌中，CaMKII 活性增加；（2）CaMKII 过表达导致心肌肥厚和 HF；（3）CaMKII 抑制（通过药物、抑制肽和基因缺失）改善心肌肥厚和 HF。患有心肌疾病的患者因 HF 和心律失常而死亡的比例相等，主要的治疗障碍是旨在增强心肌收缩的药物会促进心律失常。相比之下，抑制 CaMKII 通路似乎可以减少心律失常并改善心肌对病理刺激的反应。本文将介绍 CaMKII 的分子生理学，并讨论 CaMKII 对心肌离子通道、Ca 处理蛋白和转录的影响。本文是题为“肥厚和心力衰竭中的关键信号分子”的特刊的一部分。
