<br>Ryanodine 受体 2 (RYR2) 功能障碍会激活未折叠蛋白反应并扰乱心肌细胞成熟。,Cardiovascular Research

当前位置： X-MOL 学术 › Cardiovasc. Res. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Ryanodine 受体 2 (RYR2) 功能障碍会激活未折叠蛋白反应并扰乱心肌细胞成熟。
Cardiovascular Research ( IF 10.2 ) Pub Date : 2023-03-17 , DOI: 10.1093/cvr/cvac077
Yuxuan Guo _{1,

2,

3,

4} , Yangpo Cao ₅ , Blake D Jardin ₅ , Xiaoran Zhang ₅ , Pingzhu Zhou ₅ , Silvia Guatimosim ₆ , Junsen Lin _{1,

2,

3,

4} , Zhan Chen _{1,

2,

3,

4} , Yueyang Zhang _{1,

2,

3,

4} , Neil Mazumdar ₅ , Fujian Lu ₅ , Qing Ma ₅ , Yao-Wei Lu ₅ , Mingming Zhao _{3,

4,

7,

8} , Da-Zhi Wang ₅ , Erdan Dong _{2,

3,

4,

7,

8} , William T Pu _{5,

9}

Affiliation

目的钙处理能力是衡量心肌细胞成熟度的主要指标。 Ryanodine 受体 2 (RYR2) 是主要的钙通道，可从肌浆网/内质网 (SR/ER) 释放钙以激活心肌细胞收缩。尽管 RYR2 之前被认为是心肌细胞成熟的关键调节因子，但其机制仍不清楚。本研究的目的就是解决这个问题。方法和结果我们进行了 Cas9/AAV9 介导的体细胞诱变，以特异性敲除小鼠心肌细胞中的 RYR2。我们进行了遗传镶嵌分析，以剖析 RYR2 在心肌细胞成熟过程中的细胞自主功能。我们发现 RYR2 缺失会引发与心肌细胞成熟相关的超微结构和转录组缺陷。这些表型与 ER 应激途径的剧烈激活有关。内质网应激缓解剂牛磺熊去氧胆酸部分挽救了 RYR2 耗尽的心肌细胞的缺陷。 ATF4（一种关键的 ER 应激转录因子）的过度表达再现了 RYR2 耗尽细胞中的缺陷。 RNA-Seq 和 bioChIP-Seq 数据的综合分析表明，蛋白质生物合成相关基因是 ATF4 的主要直接下游靶标。结论 RYR2 调节的 ER 稳态对于心肌细胞成熟至关重要。严重的 ER 应激主要通过 ATF4 激活扰乱心肌细胞的成熟。 ATF4的主要下游效应基因与蛋白质生物合成相关。

"点击查看英文标题和摘要"

Ryanodine receptor 2 (RYR2) dysfunction activates the unfolded protein response and perturbs cardiomyocyte maturation.

AIMS Calcium-handling capacity is a major gauge of cardiomyocyte maturity. Ryanodine receptor 2 (RYR2) is the pre-dominant calcium channel that releases calcium from the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) to activate cardiomyocyte contraction. Although RYR2 was previously implied as a key regulator of cardiomyocyte maturation, the mechanisms remain unclear. The aim of this study is to solve this problem. METHODS AND RESULTS We performed Cas9/AAV9-mediated somatic mutagenesis to knockout RYR2 specifically in cardiomyocytes in mice. We conducted a genetic mosaic analysis to dissect the cell-autonomous function of RYR2 during cardiomyocyte maturation. We found that RYR2 depletion triggered ultrastructural and transcriptomic defects relevant to cardiomyocyte maturation. These phenotypes were associated with the drastic activation of ER stress pathways. The ER stress alleviator tauroursodeoxycholic acid partially rescued the defects in RYR2-depleted cardiomyocytes. Overexpression of ATF4, a key ER stress transcription factor, recapitulated defects in RYR2-depleted cells. Integrative analysis of RNA-Seq and bioChIP-Seq data revealed that protein biosynthesis-related genes are the major direct downstream targets of ATF4. CONCLUSION RYR2-regulated ER homeostasis is essential for cardiomyocyte maturation. Severe ER stress perturbs cardiomyocyte maturation primarily through ATF4 activation. The major downstream effector genes of ATF4 are related to protein biosynthesis.

更新日期：2023-03-17

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南