Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy
Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy
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DOI：
10.1172/jci.insight.85923
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发表时间：
2016-04-21
期刊：
影响因子：
8
通讯作者：
Judge, Daniel P.
中科院分区：
文献类型：
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作者：
Chelko, Stephen P.;Asimaki, Angeliki;Judge, Daniel P.
致心律失常性心肌病 (ACM) 的特点是连接蛋白重新分布、心律失常和进行性心肌损伤。我们之前报道过 SB216763 (SB2)，注释为 GSK3 β 抑制剂，可逆转 ACM 斑马鱼模型中的疾病表型。在这里，我们发现 SB2 在两种 ACM 小鼠模型的基线和运动反应中可预防体内心肌细胞损伤和心功能障碍。与媒介物治疗（Veh 治疗）的小鼠相比，SB2 治疗的桥粒突变小鼠的心室异位和心肌纤维化/炎症有所改善。与 Veh 治疗的 Dsg2(mut/mut) 小鼠相比，GSK3 beta 抑制改善了久坐和运动的 Dsg2(mut/mut) 小鼠的左心室功能和存活率，并且两种突变小鼠的闰盘 (ID) 蛋白分布均正常化。 GSK3 beta 在对照肌细胞中显示出弥漫性细胞质定位，但在 ACM 小鼠中显示出 ID 重新分布。 ACM 患者心肌中存在相同的 GSK3 β 重新分布，但正常心脏或其他心肌病中不存在。 SB2 降低了 ACM 小鼠中总 GSK3 β 蛋白水平，但不影响 Ser 9-GSK3 β 磷酸化。持续活跃的 GSK3 beta 会使突变小鼠的 ACM 恶化，而 ACM 心肌细胞中的 GSK3 beta shRNA 沉默可防止 ID 蛋白分布异常。这些结果强调了 GSK β 在 ACM 复杂表型中的核心作用，并提供了进一步的证据，表明药理学 GSK β 抑制可改善桥粒突变引起的心肌病。
Arrhythmogenic cardiomyopathy (ACM) is characterized by redistribution of junctional proteins, arrhythmias, and progressive myocardial injury. We previously reported that SB216763 (SB2), annotated as a GSK3 beta inhibitor, reverses disease phenotypes in a zebrafish model of ACM. Here, we show that SB2 prevents myocyte injury and cardiac dysfunction in vivo in two murine models of ACM at baseline and in response to exercise. SB2-treated mice with desmosome mutations showed improvements in ventricular ectopy and myocardial fibrosis/inflammation as compared with vehicle-treated (Veh-treated) mice. GSK3 beta inhibition improved left ventricle function and survival in sedentary and exercised Dsg2(mut/mut) mice compared with Veh-treated Dsg2(mut/mut) mice and normalized intercalated disc (ID) protein distribution in both mutant mice. GSK3 beta showed diffuse cytoplasmic localization in control myocytes but ID redistribution in ACM mice. Identical GSK3 beta redistribution is present in ACM patient myocardium but not in normal hearts or other cardiomyopathies. SB2 reduced total GSK3 beta protein levels but not phosphorylated Ser 9-GSK3 beta in ACM mice. Constitutively active GSK3 beta worsens ACM in mutant mice, while GSK3 beta shRNA silencing in ACM cardiomyocytes prevents abnormal ID protein distribution. These results highlight a central role for GSK beta in the complex phenotype of ACM and provide further evidence that pharmacologic GSK beta inhibition improves cardiomyopathies due to desmosome mutations.