Activation of PDGFRA signaling contributes to filamin C-related arrhythmogenic cardiomyopathy.
Activation of PDGFRA signaling contributes to filamin C-related arrhythmogenic cardiomyopathy.
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DOI：
10.1126/sciadv.abk0052
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发表时间：
2022-02-25
期刊：
影响因子：
13.6
通讯作者：
Mestroni L
中科院分区：
文献类型：
--
作者：
Chen SN;Lam CK;Wan YW;Gao S;Malak OA;Zhao SR;Lombardi R;Ambardekar AV;Bristow MR;Cleveland J;Gigli M;Sinagra G;Graw S;Taylor MRG;Wu JC;Mestroni L
FLNC截断突变(FlnCtv)是遗传性扩张型心肌病(DCM)的常见原因，具有发展为心律失常性心肌病的高风险。我们利用患者特异性诱导的多能干细胞来源的心肌细胞(IPSC-CMS)研究了突变的FlnC在致心律失常的扩张性心肌病(a-DCM)发病中的分子机制。我们证明了来自两个具有不同FLNCtv突变的患者的IPSC-CMS表现出心律失常和收缩受损。FLNC消融诱导了类似的表型，表明FLNCtv是功能丧失的突变。免疫共沉淀和蛋白质组学分析证实β-连环蛋白(CTNNB1)是其下游靶基因。FlnC缺乏导致CTNNB1核移位，随后激活了血小板衍生生长因子受体α(PDGFRA)途径，在a-DCM和FlNCtv患者的心脏中也观察到了这一现象。使用PDGFRA抑制剂crenolanib治疗可以改善IPSC-CMS患者的收缩功能。综上所述，我们的研究结果表明PDGFRA信号与发病机制有关，抑制这一通路是治疗FLNC相关心肌病的一种潜在策略。FlnC缺乏激活细胞间的黏附/CTNNB1/PDGFRA，导致心律失常；用crenolanib抑制挽救表型。
FLNC truncating mutations (FLNCtv) are prevalent causes of inherited dilated cardiomyopathy (DCM), with a high risk of developing arrhythmogenic cardiomyopathy. We investigated the molecular mechanisms of mutant FLNC in the pathogenesis of arrhythmogenic DCM (a-DCM) using patient-specific induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). We demonstrated that iPSC-CMs from two patients with different FLNCtv mutations displayed arrhythmias and impaired contraction. FLNC ablation induced a similar phenotype, suggesting that FLNCtv are loss-of-function mutations. Coimmunoprecipitation and proteomic analysis identified β-catenin (CTNNB1) as a downstream target. FLNC deficiency induced nuclear translocation of CTNNB1 and subsequently activated the platelet-derived growth factor receptor alpha (PDGFRA) pathway, which were also observed in human hearts with a-DCM and FLNCtv. Treatment with the PDGFRA inhibitor, crenolanib, improved contractile function of patient iPSC-CMs. Collectively, our findings suggest that PDGFRA signaling is implicated in the pathogenesis, and inhibition of this pathway is a potential therapeutic strategy in FLNC-related cardiomyopathies. FLNC deficiency activates cell-cell adhesion/CTNNB1/PDGFRA, causing arrhythmias; inhibition with crenolanib rescues the phenotype.
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