Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome
文献类型：期刊论文
| 作者 | Guo, FF; Sun, YX; Wang, XC; Wang, H; Wang, J; Gong, TY; Chen, XZ; Zhang, P; Su, L; Fu, GS |
| 刊名 | CIRCULATION RESEARCH
 |
| 出版日期 | 2019 |
| 卷号 | 124期号:1页码:66-78 |
| ISSN号 | 0009-7330 |
| 英文摘要 | Rationale: Short QT syndrome (SQT) is a rare but arrhythmogenic disorder featured by shortened ventricular repolarization and a propensity toward life-threatening ventricular arrhythmias and sudden cardiac death. Objective: This study aimed to investigate the single-cell mechanism of SQT using patient-specific and genecorrected induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Methods and Results: One SQT patient carrying missense mutation T618I in potassium voltage-gated channel subfamily H member 2 (KCNH2) was recruited as well as 2 healthy control subjects in this study. Control and SQT patient-specific iPSCs were generated from skin fibroblasts using nonintegrated Sendai virus. The KCNH2 T618I mutation was corrected by genome editing in SQT iPSC lines to generate isogenic controls. All iPSCs were differentiated into iPSC-CMs using monolayer-based differentiation protocol. SQT iPSC-CMs exhibited abnormal action potential phenotype featured by shortened action potential duration and increased beat-beat interval variability, when compared with control and gene-corrected iPSC-CMs. Furthermore, SQT iPSC-CMs showed KCNH2 gain-of-function with increased rapid delayed rectifying potassium current (I Kr) density and enhanced membrane expression. Gene expression profiling of iPSC-CMs exhibited a differential cardiac ionchannel gene expression profile of SQT. Moreover, QTc of SQT patient and action potential durations of SQT iPSC-CMs were both normalized by quinidine, indicating that quinidine is beneficial to KCNH2 T618I of SQT. Importantly, shortened action potential duration phenotype observed in SQT iPSC-CMs was effectively rescued by a short-peptide scorpion toxin BmKKx2 with a mechanism of targeting KCNH2. Conclusions: We demonstrate that patient-specific and gene-corrected iPSC-CMs are able to recapitulate singlecell phenotype of SQT, which is caused by the gain-of-function mutation KCNH2 T618I. These findings will help elucidate the mechanisms underlying SQT and discover therapeutic drugs for treating the disease by using peptide toxins as lead compounds. (Circ Res. 2019; 124: 66-78. DOI: 10.1161/ CIRCRESAHA. 118.313518.) |
| 语种 | 英语 |
| 源URL | [http://ir.kiz.ac.cn:8080/handle/152453/12449]  |
| 专题 | 昆明动物研究所_动物毒素室 |
| 推荐引用方式 GB/T 7714 | Guo, FF,Sun, YX,Wang, XC,et al. Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome[J]. CIRCULATION RESEARCH,2019,124(1):66-78. |
| APA | Guo, FF.,Sun, YX.,Wang, XC.,Wang, H.,Wang, J.,...&Liang, P.(2019).Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome.CIRCULATION RESEARCH,124(1),66-78. |
| MLA | Guo, FF,et al."Patient-Specific and Gene-Corrected Induced Pluripotent Stem Cell-Derived Cardiomyocytes Elucidate Single-Cell Phenotype of Short QT Syndrome".CIRCULATION RESEARCH 124.1(2019):66-78. |
入库方式： OAI收割
来源：昆明动物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。