病毒递送的 CMYA5 可增强心脏二联体的组装

IF 26.8 1区 医学 Q1 ENGINEERING, BIOMEDICAL
Fujian Lu, Carter Liou, Qing Ma, Zexuan Wu, Bingqing Xue, Yu Xia, Shutao Xia, Michael A. Trembley, Anna Ponek, Wenjun Xie, Kevin Shani, Raul H. Bortolin, Maksymilian Prondzynski, Paul Berkson, Xiaoran Zhang, Francisco J. Naya, Kenneth C. Bedi, Kenneth B. Margulies, Donghui Zhang, Kevin K. Parker, William T. Pu
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引用次数: 0

摘要

从人类诱导多能干细胞(hiPSC-CMs)中提取的心肌细胞缺乏高效激发-收缩耦合所必需的纳米级结构。这种被称为二联体的纳米结构在心力衰竭中经常被破坏。我们在这里发现,心肌病相关 5(CMYA5)--一种建立二联体的主蛋白--的表达减少导致了心衰中的二联体紊乱和 hiPSC-CMs 中的二联体组装受损,而一种适合通过腺相关病毒递送的小型化 CMYA5 能显著改善二联体结构,并使压力过载下的心脏功能恢复正常。在 hiPSC-CMs 中,小型化形式的 CMYA5 增加了收缩力,改善了 Ca2+ 处理,并增强了肌节 Z 线与雷诺丁受体 2(一种介导肌浆释放储存的 Ca2+ 的蛋白质)的排列。我们的研究结果阐明了病变心肌细胞中二联体结构受损的机制,并提出了在心脏病和 hiPSC-CMs 培育过程中促进二联体组装和稳定性的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Virally delivered CMYA5 enhances the assembly of cardiac dyads

Virally delivered CMYA5 enhances the assembly of cardiac dyads

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) lack nanoscale structures essential for efficient excitation–contraction coupling. Such nanostructures, known as dyads, are frequently disrupted in heart failure. Here we show that the reduced expression of cardiomyopathy-associated 5 (CMYA5), a master protein that establishes dyads, contributes to dyad disorganization in heart failure and to impaired dyad assembly in hiPSC-CMs, and that a miniaturized form of CMYA5 suitable for delivery via an adeno-associated virus substantially improved dyad architecture and normalized cardiac function under pressure overload. In hiPSC-CMs, the miniaturized form of CMYA5 increased contractile forces, improved Ca2+ handling and enhanced the alignment of sarcomere Z-lines with ryanodine receptor 2, a protein that mediates the sarcoplasmic release of stored Ca2+. Our findings clarify the mechanisms responsible for impaired dyad structure in diseased cardiomyocytes, and suggest strategies for promoting dyad assembly and stability in heart disease and during the derivation of hiPSC-CMs.

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来源期刊
Nature Biomedical Engineering
Nature Biomedical Engineering Medicine-Medicine (miscellaneous)
CiteScore
45.30
自引率
1.10%
发文量
138
期刊介绍: Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.
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