Department of Medicine II, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
Curr Med Chem. 2014;21(11):1320-9. doi: 10.2174/0929867321666131227130218.
In the face of an aging population and thereby an increasing number of patients suffering from heart rhythm diseases development of therapeutic agents is one of the major challenges in modern biomedical research. Antiarrhythmic drug discovery was mainly hindered by the limited knowledge of the molecular underpinnings of cardiac electrophysiology in health and disease. In recent years, the zebrafish has emerged as an effective model organism to dissect the pathology of human disorders in particular in the area of cardiovascular diseases. Especially, certain aspects of cardiac electrophysiology of the zebrafish such as action potential or heart rate are similar to that of humans. The zebrafish shares many features of human physiology and body plan but it develops extra-uterine and is initially transparent, allowing detailed and comprehensive characterization of cardiac development and function in vivo. Moreover, zebrafish are well amenable to large-scale forward and reverse functional genomics approaches, which has led to the identification of numerous novel genetic key-players and potential targets of cardiac disease. In this context, several zebrafish lines with mutations in defined ion channels have emerged as novel vertebrate models for human arrhythmia disorders such as long or short QT syndrome. In addition, due to its size and the high number of progeny, zebrafish are very suitable for rapid in vivo analysis of the bioactivity of small molecules and their therapeutic potential, especially in the context of cardiovascular diseases such as arrhythmias. In this review we highlight an assortment of established zebrafish models that enable the dissection of human heart rhythm disorders and the potential of this model system for the discovery of novel antiarrhythmic targets and drugs.
面对人口老龄化以及由此导致的心律失常疾病患者数量不断增加，开发治疗药物是现代生物医学研究的主要挑战之一。抗心律失常药物的发现主要受到心脏电生理学在健康和疾病中的分子基础的知识有限的阻碍。近年来，斑马鱼已成为一种有效的模式生物，可以剖析人类疾病的病理学，特别是在心血管疾病领域。特别是，斑马鱼的某些心脏电生理学方面，如动作电位或心率，与人类相似。斑马鱼具有许多人类生理学和身体结构的特征，但它在体外发育并且最初是透明的，允许对心脏发育和功能进行详细和全面的体内特征描述。此外，斑马鱼非常适合大规模的正向和反向功能基因组学方法，这导致了许多新的遗传关键因素和心脏疾病的潜在靶点的鉴定。在这种情况下，几种在特定离子通道中发生突变的斑马鱼系已成为人类心律失常疾病（如长 QT 或短 QT 综合征）的新型脊椎动物模型。此外，由于其体型和大量后代，斑马鱼非常适合小分子的体内快速分析其生物活性及其治疗潜力，特别是在心律失常等心血管疾病的背景下。在这篇综述中，我们强调了一系列已建立的斑马鱼模型，这些模型可以剖析人类心律失常疾病，以及该模型系统在发现新型抗心律失常靶点和药物方面的潜力。
