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人类PLN-R14del心肌病内质网钙负荷改变。

Altered endoplasmic reticulum calcium loading in human PLN-R14del cardiomyopathy.

作者信息

Borbein Willem, Dahmlos Lukas, Saleem Umber, Reinsch Marina, Braren Ingke, Schulze Thomas, Klampe Birgit, Cuello Friederike, Stenzig Justus, Eschenhagen Thomas, Hansen Arne

机构信息

Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Lübeck/Kiel, Berlin, Germany.

出版信息

Front Cell Dev Biol. 2025 Jul 28;13:1627985. doi: 10.3389/fcell.2025.1627985. eCollection 2025.

DOI:10.3389/fcell.2025.1627985
PMID:40791987
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12336144/
Abstract

The phospholamban (PLN) R14del genetic variant causes dilated cardiomyopathy. Previous studies suggest involvement of the ER stress response and impairment of ER-related signaling pathways such as autophagy. In this study, human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from an unrelated control subject, a PLN-R14del patient, and a corresponding isogenic control were transduced with adeno-associated virus serotype 6 (AAV6) encoding the endoplasmic reticulum calcium sensor CEPIAer. Indicator compounds for the modulation of ER calcium homeostasis showed similar characteristic effects on CEPIAer fluorescence intensity in engineered heart tissues (EHTs) from all three cell lines, validating CEPIAer fluorescence intensity as a surrogate for ER calcium loading. Cytoplasmic calcium loading induced by high extracellular calcium concentration revealed subtle alterations in PLN-R14del that were consistent with higher ER calcium loading. FACS analyses of dissociated cardiomyocytes confirmed higher ER calcium load. Taken together, this study provides evidence for altered ER calcium loading as a new disease mechanism in PLN-R14del cardiomyopathy.

摘要

磷酸受磷蛋白（PLN）R14del基因变异会导致扩张型心肌病。先前的研究表明内质网应激反应以及自噬等内质网相关信号通路受损与之有关。在本研究中，用编码内质网钙传感器CEPIAer的腺相关病毒血清型6（AAV6）转导来自一名无关对照受试者、一名PLN-R14del患者以及相应同基因对照的人诱导多能干细胞（hiPSC）衍生的心肌细胞（CM）。用于调节内质网钙稳态的指示剂化合物对来自所有三种细胞系的工程心脏组织（EHT）中的CEPIAer荧光强度显示出相似的特征性影响，证实CEPIAer荧光强度可作为内质网钙负荷的替代指标。高细胞外钙浓度诱导的细胞质钙负荷显示PLN-R14del存在细微变化，这与较高的内质网钙负荷一致。对解离的心肌细胞进行的流式细胞术分析证实内质网钙负荷较高。综上所述，本研究为内质网钙负荷改变作为PLN-R14del心肌病的一种新的疾病机制提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/e3a22bbf9b95/fcell-13-1627985-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/00efb2ad1664/fcell-13-1627985-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/f95aaab32a6c/fcell-13-1627985-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/bccdc0cf283b/fcell-13-1627985-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/ed328ec83d8e/fcell-13-1627985-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/19929eb76263/fcell-13-1627985-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/e3a22bbf9b95/fcell-13-1627985-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/00efb2ad1664/fcell-13-1627985-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/f95aaab32a6c/fcell-13-1627985-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/bccdc0cf283b/fcell-13-1627985-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/ed328ec83d8e/fcell-13-1627985-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/19929eb76263/fcell-13-1627985-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1464/12336144/e3a22bbf9b95/fcell-13-1627985-g006.jpg

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本文引用的文献

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Age-related penetrance of phospholamban p.Arg14del cardiomyopathy.受年龄影响的磷酸肌浆蛋白p.Arg14del心肌病的外显率
Eur J Heart Fail. 2025 Apr 22. doi: 10.1002/ejhf.3672.
2
Dilated cardiomyopathy variant R14del increases phospholamban pentamer stability, blunting dynamic regulation of calcium.扩张型心肌病变体R14del增加受磷蛋白五聚体稳定性，削弱钙的动态调节。
J Biol Chem. 2025 Feb;301(2):108118. doi: 10.1016/j.jbc.2024.108118. Epub 2024 Dec 21.
3
The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion.
肌浆网磷蛋白 R14del 通过损害自噬体-溶酶体融合产生致病聚集体。
Cell Mol Life Sci. 2024 Nov 11;81(1):450. doi: 10.1007/s00018-024-05471-1.
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Induced pluripotent stem cell-derived cardiomyocyte in vitro models: benchmarking progress and ongoing challenges.诱导多能干细胞衍生的心肌细胞体外模型：基准进展与现存挑战
Nat Methods. 2025 Jan;22(1):24-40. doi: 10.1038/s41592-024-02480-7. Epub 2024 Nov 8.
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Early consequences of the phospholamban mutation PLN-R14del in a transgenic mouse model.PLN-R14del 突变在转基因小鼠模型中的早期后果。
Acta Physiol (Oxf). 2024 Mar;240(3):e14082. doi: 10.1111/apha.14082. Epub 2024 Jan 12.
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The Concise Guide to PHARMACOLOGY 2023/24: Transporters.《药理学简明指南 2023/24 年版：转运蛋白》
Br J Pharmacol. 2023 Oct;180 Suppl 2:S374-S469. doi: 10.1111/bph.16182.
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The Concise Guide to PHARMACOLOGY 2023/24: Ion channels.《药理学简明指南 2023/24 年版》：离子通道。
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8
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Electrophysiological and calcium-handling development during long-term culture of human-induced pluripotent stem cell-derived cardiomyocytes.人诱导多能干细胞衍生心肌细胞长期培养过程中的电生理和钙处理发育。
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