Nonaka Miki, Morimoto Sachio
Miki Nonaka, Sachio Morimoto, Department of Clinical Pharmacology, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan.
World J Cardiol. 2014 Dec 26;6(12):1245-51. doi: 10.4330/wjc.v6.i12.1245.
Cardiomyopathy is a disease of myocardium categorized into three major forms, hypertrophic (HCM), dilated (DCM) and restrictive cardiomyopathy (RCM), which has recently been demonstrated to be a monogenic disease due to mutations in various proteins expressed in cardiomyocytes. Mutations in HCM and RCM typically increase the myofilament sensitivity to cytoplasmic Ca(2+), leading to systolic hyperfunction and diastolic dysfunction. In contrast, mutations in DCM typically decrease the myofilament sensitivity to cytoplasmic Ca(2+) and/or force generation/transmission, leading to systolic dysfunction. Creation of genetically-manipulated transgenic and knock-in animals expressing mutant proteins exogenously and endogenously, respectively, in their hearts provides valuable animal models to discover the molecular and cellular mechanisms for pathogenesis and promising therapeutic strategy in vivo. Recently, cardiomyocytes have been differentiated from patient's induced pluripotent stem cells as a model of inherited cardiomyopathies in vitro. In this review, we provide overview of experimental models of cardiomyopathies with a focus on revealed molecular and cellular pathogenic mechanisms and potential therapeutics.
心肌病是一种心肌疾病，主要分为三种类型：肥厚型心肌病（HCM）、扩张型心肌病（DCM）和限制型心肌病（RCM）。最近研究表明，由于心肌细胞中各种蛋白质发生突变，心肌病属于单基因疾病。HCM和RCM中的突变通常会增加肌丝对细胞质Ca(2+)的敏感性，导致收缩功能亢进和舒张功能障碍。相反，DCM中的突变通常会降低肌丝对细胞质Ca(2+)的敏感性和/或力的产生/传递，导致收缩功能障碍。分别在心脏中外源和内源表达突变蛋白的基因工程转基因和敲入动物的创建，为发现发病机制的分子和细胞机制以及体内有前景的治疗策略提供了有价值的动物模型。最近，心肌细胞已从患者的诱导多能干细胞分化而来，作为体外遗传性心肌病的模型。在这篇综述中，我们概述了心肌病的实验模型，重点是揭示的分子和细胞致病机制以及潜在的治疗方法。
