Department of Physiology, University of Debrecen, Nagyerdei krt. 98. H-4012 Debrecen, Hungary.
Curr Med Chem. 2011;18(24):3707-13. doi: 10.2174/092986711796642409.
Therapeutic strategy for cardiac arrhythmias has undergone a remarkable change during the last decades. Currently implantable cardioverter defibrillator therapy is considered to be the most effective therapeutic method to treat malignant arrhythmias. Some even argue that there is no room for antiarrhythmic drug therapy in the age of implantable cardioverter defibrillators. However, in clinical practice, antiarrhythmic drug therapies are frequently needed, because implantable cardioverter defibrillators are not effective in certain types of arrhythmias (i.e. premature ventricular beats or atrial fibrillation). Furthermore, given the staggering cost of device therapy, it is economically imperative to develop alternative effective treatments. Cardiac ion channels are the target of a number of current treatment strategies, but therapies based on ion channel blockers only resulted in moderate success. Furthermore, these drugs are associated with an increased risk of proarrhythmia, systemic toxicity, and increased defibrillation threshold. In many cases, certain ion channel blockers were found to increase mortality. Other drug classes such as ßblockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and statins appear to have proven efficacy for reducing cardiac mortality. These facts forced researchers to shift the focus of their research to molecular targets that act upstream of ion channels. One of these potential targets is calcium/calmodulin-dependent kinase II (CaMKII). Several lines of evidence converge to suggest that CaMKII inhibition may provide an effective treatment strategy for heart diseases. (1) Recent studies have elucidated that CaMKII plays a key role in modulating cardiac function and regulating hypertrophy development. (2) CaMKII activity has been found elevated in the failing hearts from human patients and animal models. (3) Inhibition of CaMKII activity has been shown to mitigate hypertrophy, prevent functional remodeling and reduce arrhythmogenic activity. In this review, we will discuss the structural and functional properties of CaMKII, the modes of its activation and the functional consequences of CaMKII activity on ion channels.
在过去的几十年中，心脏心律失常的治疗策略发生了显著变化。目前，植入式心脏复律除颤器治疗被认为是治疗恶性心律失常最有效的治疗方法。有些人甚至认为，在植入式心脏复律除颤器时代，抗心律失常药物治疗已经没有空间。然而，在临床实践中，经常需要抗心律失常药物治疗，因为植入式心脏复律除颤器在某些类型的心律失常（即室性早搏或心房颤动）中并不有效。此外，鉴于设备治疗的惊人成本，开发替代有效治疗方法在经济上是必要的。心脏离子通道是许多当前治疗策略的目标，但基于离子通道阻滞剂的治疗方法仅取得了中等成功。此外，这些药物与心律失常风险增加、全身毒性和除颤阈值增加有关。在许多情况下，某些离子通道阻滞剂被发现会增加死亡率。其他药物类别，如β受体阻滞剂、血管紧张素转换酶抑制剂、醛固酮拮抗剂和他汀类药物，似乎已被证明可有效降低心脏死亡率。这些事实迫使研究人员将研究重点转移到作用于离子通道上游的分子靶点上。其中一个潜在的靶点是钙/钙调蛋白依赖性激酶 II（CaMKII）。有几条证据表明，CaMKII 抑制可能为心脏病提供有效的治疗策略。（1）最近的研究阐明了 CaMKII 在调节心脏功能和调节肥大发育方面起着关键作用。（2）已经在人类患者和动物模型的衰竭心脏中发现 CaMKII 活性升高。（3）抑制 CaMKII 活性已被证明可以减轻肥大、防止功能重塑和减少心律失常活性。在这篇综述中，我们将讨论 CaMKII 的结构和功能特性、其激活方式以及 CaMKII 活性对离子通道的功能后果。
