SARS-CoV-2尖峰蛋白是一种β-肾上腺素能受体激动剂：长COVID心脏后遗症的潜在机制。

IF 9 2区医学 Q1 MEDICINE, GENERAL & INTERNAL

Journal of Internal Medicine Pub Date : 2024-07-29 DOI:10.1111/joim.20000

Xiangning Deng, Hongtu Cui, Hao Liang, Xinyu Wang, Haiyi Yu, Jingjia Wang, Wenyao Wang, Dongyang Liu, Youyi Zhang, Erdan Dong, Yida Tang, Han Xiao

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引用次数: 0

摘要

背景：目前，冠状病毒病-19-心血管综合征（PASC-CVS）急性后遗症的病理生理机制仍不清楚：PASC-CVS 患者的严重急性呼吸系统综合征-冠状病毒 2 尖峰蛋白 S1 循环水平明显高于非 PASC-CVS 患者和健康对照组。此外，血浆尖峰蛋白 S1 浓度高的人心率升高，低频正常，这表明心脏 β 肾上腺素能受体（β-AR）功能亢进。微尺度热泳（MST）测定显示，尖峰蛋白与β1-和β2-AR结合，但不与D1-多巴胺受体结合。这些相互作用被β1-和β2-AR阻断剂阻断。β-AR突变体的分子对接和MST测定显示，尖峰蛋白与两种β-AR的胞外环2相互作用。在心肌细胞中，无论有无肾上腺素，尖峰蛋白都能剂量依赖性地增加环磷酸腺苷的产生，这表明它对β-ARs具有异构作用：结论：严重急性呼吸系统综合征-冠状病毒-2尖峰蛋白是一种异位β-AR激动剂，可导致心脏β-AR亢进，从而导致PASC-CVS。

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SARS-CoV-2 spike protein acts as a β-adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID

Background

Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown.

Methods and results

Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac β-adrenergic receptor (β-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to β₁- and β₂-AR, but not to D1-dopamine receptor. These interactions were blocked by β₁- and β₂-AR blockers. Molecular docking and MST assay of β-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both β-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on β-ARs.

Conclusion

Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric β-AR agonist, leading to cardiac β-AR hyperactivity, thus contributing to PASC-CVS.

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来源期刊

Journal of Internal Medicine 医学-医学：内科

CiteScore

22.00

自引率

0.90%

发文量

176

审稿时长

4-8 weeks

期刊介绍： JIM – The Journal of Internal Medicine, in continuous publication since 1863, is an international, peer-reviewed scientific journal. It publishes original work in clinical science, spanning from bench to bedside, encompassing a wide range of internal medicine and its subspecialties. JIM showcases original articles, reviews, brief reports, and research letters in the field of internal medicine.