The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy.
The hippo pathway is activated and is a causal mechanism for adipogenesis in arrhythmogenic cardiomyopathy.
复制标题
河马途径被激活，是心律失常性心肌病中脂肪形成的因果机制。
DOI：
10.1161/circresaha.114.302810
复制
发表时间：
2014-01-31
影响因子：
20.1
通讯作者：
Marian AJ
中科院分区：
文献类型：
--
作者：
Chen SN;Gurha P;Lombardi R;Ruggiero A;Willerson JT;Marian AJ
闰盘（ID）蛋白（如斑嗜蛋白2（PKP 2））的突变可引起致瘤性心肌病（AC）。AC的特征是心肌细胞被纤维脂肪细胞替代、心功能障碍、心律失常和猝死。阐明AC的分子发病机制。包括信号分子在内的选定ID蛋白的定位和水平在患有AC的人心脏中显著降低。在人类心脏、AC的Nkx2.5-Cre：DspW/F和Myh 6：Jup小鼠模型中，ID的蛋白质组分的改变与上游Hippo分子的激活相关，并且在血小板亲和素2（PKP 2）敲低HL-1心肌细胞（HL-1 PKP 2：shRNA）中。活性PKC-α水平降低，其活性需要PKP 2。相反，神经纤维蛋白（NF 2或Merlin），一种Hippo通路上游的分子，被PKC-α灭活，被激活。因此，下游Hippo分子MST 1/2、LATS 1/2和雅普（后者是该途径的效应物）被磷酸化。免疫共沉淀检测到pYAP、pβ-catenin和JUP的结合，后者从连接处易位。RNA测序、转录本qPCR和报告基因测定分别显示TEAD和TCF 7 L2（Hippo和经典Wnt信号传导的转录因子）的抑制活性。相反，脂肪形成增强。在HL-1 PKP 2：shRNA心肌细胞中，同时KD雅普上游分子Lats 1/2，挽救了雅普和β-连环蛋白的失活和脂肪生成。ID的分子重塑导致Hippo通路的致病性激活、经典Wnt信号传导的抑制和AC中脂肪生成的增强。这些发现为AC的发病机制提供了新的机制。
Mutations in the intercalated disc (ID) proteins, such as plakophilin 2 (PKP2) cause arrhythmogenic cardiomyopathy (AC). AC is characterized by the replacement of cardiac myocytes by fibro-adipocytes, cardiac dysfunction, arrhythmias and sudden death. To delineate the molecular pathogenesis of AC. Localization and levels of selected ID proteins including signaling molecules were markedly reduced in the human hearts with AC. Altered protein constituents of IDs was associated with activation of the upstream Hippo molecules in the human hearts, Nkx2.5-Cre:DspW/F and Myh6:Jup mouse models of AC, and in the plakophilin 2 (PKP2) knock down HL-1 myocytes (HL-1PKP2:shRNA). Level of active PKC-α, which requires PKP2 for activity, was reduced. In contrast, neurofibromin (NF2 or Merlin), a molecule upstream to the Hippo pathway, which is inactivated by PKC-α, was activated. Consequently, the downstream Hippo molecules MST1/2, LATS1/2 and YAP; the latter is the effector of the pathway, were phosphorylated. Co-immunoprecipitation detected binding of pYAP, pβ-catenin, and JUP, the latter translocated from the junction. RNA sequencing, transcript qPCR and reporter assays showed suppressed activity of TEAD and TCF7L2, transcription factors of the Hippo and the canonical Wnt signaling, respectively. In contrast, adipogenesis was enhanced. Simultaneous KD of Lats1/2, molecules upstream to YAP, rescued inactivation of YAP and β-catenin and adipogenesis in the HL-1PKP2:shRNA myocytes. Molecular remodeling of the IDs leads to pathogenic activation of the Hippo pathway, suppression of the canonical Wnt signaling and enhanced adipogenesis in AC. The findings offer novel mechanisms for the pathogenesis of AC.