Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy.
Identification of a new modulator of the intercalated disc in a zebrafish model of arrhythmogenic cardiomyopathy.
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DOI：
10.1126/scitranslmed.3008008
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发表时间：
2014-06-11
影响因子：
17.1
通讯作者：
Saffitz JE
中科院分区：
文献类型：
--
作者：
Asimaki A;Kapoor S;Plovie E;Karin Arndt A;Adams E;Liu Z;James CA;Judge DP;Calkins H;Churko J;Wu JC;MacRae CA;Kléber AG;Saffitz JE
心律失常性心肌病（ACM）的特征是频繁的心律失常。为了阐明潜在的机制和发现潜在的化学修饰剂，我们建立了一个斑马鱼模型的ACM与心肌细胞特异性表达的人类2057 del 2突变的基因编码斑珠蛋白。高通量筛选确定SB 216763为疾病表型的抑制因子。早期SB 216763治疗可预防心力衰竭并降低鱼类模型的死亡率。表达2057 del 2斑珠蛋白的斑马鱼心室肌细胞显示INa和IK 1电流密度降低70 - 80%，SB 216763使其正常化。表达2057 del 2斑珠蛋白的新生大鼠心室肌细胞重现了ACM患者的病理生物学特征，所有这些都被SB 216763逆转或阻止。SB 216763观察到的逆向重塑涉及斑珠蛋白、连接蛋白43和Nav1.5的显著亚细胞再分布，但其总细胞含量没有变化，这意味着蛋白质运输到闰盘的缺陷。为了进一步支持这一机制，我们观察到SB 216763-SAP 97（已知介导Nav1.5和Kir2.1正向运输的蛋白质）在表达2057 del 2斑珠蛋白的大鼠心肌细胞中的可逆异常亚细胞分布，以及在来自两个具有斑嗜蛋白-2突变的ACM先证者的诱导多能干细胞的心肌细胞中的分布。这些观察结果指出，闰盘蛋白的异常运输是ACM肌细胞损伤和电异常的中心机制。
Arrhythmogenic cardiomyopathy (ACM) is characterized by frequent cardiac arrhythmias. To elucidate the underlying mechanisms and discover potential chemical modifiers, we created a zebrafish model of ACM with cardiac myocyte–specific expression of the human 2057del2 mutation in the gene encoding plakoglobin. A high-throughput screen identified SB216763 as a suppressor of the disease phenotype. Early SB216763 therapy prevented heart failure and reduced mortality in the fish model. Zebrafish ventricular myocytes that expressed 2057del2 plakoglobin exhibited 70 to 80% reductions in INa and IK1 current densities, which were normalized by SB216763. Neonatal rat ventricular myocytes that expressed 2057del2 plakoglobin recapitulated pathobiological features seen in patients with ACM, all of which were reversed or prevented by SB216763. The reverse remodeling observed with SB216763 involved marked subcellular redistribution of plakoglobin, connexin 43, and Nav1.5, but without changes in their total cellular content, implicating a defect in protein trafficking to intercalated discs. In further support of this mechanism, we observed SB216763-reversible, abnormal subcellular distribution of SAP97 (a protein known to mediate forward trafficking of Nav1.5 and Kir2.1) in rat cardiac myocytes expressing 2057del2 plakoglobin and in cardiac myocytes derived from induced pluripotent stem cells from two ACM probands with plakophilin-2 mutations. These observations pinpoint aberrant trafficking of intercalated disc proteins as a central mechanism in ACM myocyte injury and electrical abnormalities.
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运动增加了与年龄相关的外观和心律不齐的风险，在心律不齐的右心室发育不良/心肌病相关的脱发突变携带者中。
影响因子：
24
作者：
James, Cynthia A.;Bhonsale, Aditya;Tichnell, Crystal;Murray, Brittney;Russell, Stuart D.;Tandri, Harikrishna;Tedford, Ryan J.;Judge, Daniel P.;Calkins, Hugh
通讯作者：
Calkins, Hugh
DOI：
10.1007/978-1-62703-511-8_7
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Churko JM;Burridge PW;Wu JC
通讯作者：
Wu JC
影响因子：
7.8
作者：
Ruiz, P;Brinkmann, V;Birchmeier, W
通讯作者：
Birchmeier, W
影响因子：
20.1
作者：
Gavillet, Bruno;Rougier, Jean-Sebastien;Abriel, Hugues
通讯作者：
Abriel, Hugues
影响因子：
10.8
作者：
Rizzo, Stefania;Lodder, Elisabeth M.;Bezzina, Connie R.
通讯作者：
Bezzina, Connie R.