Loiben Alexander M, Chien Wei-Ming, Friedman Clayton E, Chao Leslie S-L, Weber Gerhard, Goldstein Alex, Sniadecki Nathan, Murry Charles E, Yang Kai-Chun
Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine, Seattle, WA, USA.
Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA.
bioRxiv. 2023 Jan 25:2023.01.24.525458. doi: 10.1101/2023.01.24.525458.
Missense mutations in myosin heavy chain 7 ( ) are a common cause of hyper-trophic cardiomyopathy (HCM), but the molecular mechanisms underlying -based HCM remain unclear. In this work, we generated cardiomyocytes derived from isogenic human induced pluripotent stem cells to model the heterozygous pathogenic missense variant, E848G, which is associated with left ventricular hypertrophy and adultonset systolic dysfunction. increased cardiomyocyte size and reduced the maximum twitch forces of engineered heart tissue, consistent with the systolic dysfunction in E848G HCM patients. Interestingly, cardiomyocytes more frequently underwent apoptosis that was associated with increased p53 activity relative to controls. However, genetic ablation of did not rescue cardiomyocyte survival or restore engineered heart tissue twitch force, indicating cardiomyocyte apoptosis and contractile dysfunction are p53-independent. Overall, our findings suggest that cardiomyocyte apoptosis plays an important role in the HCM phenotype and that future efforts to target p53-independent cell death pathways may be beneficial for the treatment of HCM patients with systolic dysfunction.
肌球蛋白重链7（ ）中的错义突变是肥厚型心肌病（HCM）的常见病因，但基于 的HCM潜在分子机制仍不清楚。在这项研究中，我们从同基因人诱导多能干细胞中生成心肌细胞，以模拟杂合致病性错义变体E848G，该变体与左心室肥厚和成人发病的收缩功能障碍有关。 增加了心肌细胞大小，并降低了工程化心脏组织的最大收缩力，这与E848G HCM患者的收缩功能障碍一致。有趣的是，与对照相比， 心肌细胞更频繁地发生凋亡，这与p53活性增加有关。然而， 的基因敲除并未挽救心肌细胞存活或恢复工程化心脏组织的收缩力，表明 心肌细胞凋亡和收缩功能障碍是p53非依赖性的。总体而言，我们的研究结果表明，心肌细胞凋亡在 HCM表型中起重要作用，未来针对p53非依赖性细胞死亡途径的努力可能对治疗有收缩功能障碍的HCM患者有益。
