Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy.
Human iPSC model reveals a central role for NOX4 and oxidative stress in Duchenne cardiomyopathy.
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DOI：
10.1016/j.stemcr.2021.12.019
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发表时间：
2022-02-08
影响因子：
5.9
通讯作者：
Sampaolesi M
中科院分区：
文献类型：
--
作者：
Duelen R;Costamagna D;Gilbert G;De Waele L;Goemans N;Desloovere K;Verfaillie CM;Sipido KR;Buyse GM;Sampaolesi M
杜氏肌营养不良症（DMD）是由肌营养不良蛋白基因突变引起的进行性肌肉疾病。心肌病是早期死亡的主要原因。我们使用DMD患者特异性人类诱导多能干细胞（hiPSC）来模拟心肌病特征并揭示新的病理学见解。从DMD hiPSC分化的心肌细胞（CM）显示出由于由去极化线粒体引起的显著升高的细胞内活性氧（ROS）和增加的NADPH氧化酶4（NOX 4）而增强的过早细胞死亡。Dystrophin的CRISPR-Cas9校正恢复了正常的ROS水平。通过N-乙酰基-L-半胱氨酸（NAC）、阿他鲁伦（PTC 124）和艾地苯醌减少ROS改善了hiPSC-CM存活。我们表明，DMD hiPSC-CM中的氧化应激通过刺激三磷酸腺苷（ATP）的产生来抵消。ATP可与NOX 4结合，部分抑制ROS的产生。考虑到DMD心肌病的复杂性和早期细胞应激反应，我们提出靶向ROS产生和预防NOX 4对DMD CM的不利影响作为有前途的治疗策略。未治疗DMD hiPSC-CM的细胞过早死亡DMD hiPSC-CM显示氧化应激水平和NOX 4增加艾地苯醌抑制ROS产生NOX 4对疾病表型有益在这篇文章中，Duelen及其同事表明，基于hiPSC的体外模型揭示了ROS产生NOX 4是Duchenne心肌病中氧化应激的重要贡献者。他们提供的证据表明，通过NAC清除剂减少ROS，通过阿他卢仑（PTC 124）重新表达部分肌营养不良蛋白，以及通过艾地苯醌增强线粒体电子传递链功能，改善了DMD hiPSC-CM的细胞存活率。
Duchenne muscular dystrophy (DMD) is a progressive muscle disorder caused by mutations in the Dystrophin gene. Cardiomyopathy is a major cause of early death. We used DMD-patient-specific human induced pluripotent stem cells (hiPSCs) to model cardiomyopathic features and unravel novel pathologic insights. Cardiomyocytes (CMs) differentiated from DMD hiPSCs showed enhanced premature cell death due to significantly elevated intracellular reactive oxygen species (ROS) resulting from depolarized mitochondria and increased NADPH oxidase 4 (NOX4). CRISPR-Cas9 correction of Dystrophin restored normal ROS levels. ROS reduction by N-acetyl-L-cysteine (NAC), ataluren (PTC124), and idebenone improved hiPSC-CM survival. We show that oxidative stress in DMD hiPSC-CMs was counteracted by stimulating adenosine triphosphate (ATP) production. ATP can bind to NOX4 and partially inhibit the ROS production. Considering the complexity and the early cellular stress responses in DMD cardiomyopathy, we propose targeting ROS production and preventing detrimental effects of NOX4 on DMD CMs as promising therapeutic strategy. Human iPSC-based in vitro model for studying Duchenne cardiomyopathy Premature cell death of untreated DMD hiPSC-CMs DMD hiPSC-CMs show increased oxidative stress levels and NOX4 Inhibition of ROS-producing NOX4 by idebenone is beneficial for disease phenotype In this article, Duelen and colleagues show that a hiPSC-based in vitro model reveals ROS-producing NOX4 as an important contributor of oxidative stress in Duchenne cardiomyopathy. They provide evidence that ROS reduction by a NAC scavenger, partial Dystrophin re-expression by ataluren (PTC124), and enhancing mitochondrial electron transport chain function by idebenone improved cell survival of DMD hiPSC-CMs.
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