Abstract：
BACKGROUND: Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown.
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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
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尚不清楚。
结果：与非PASC-CVS患者和健康对照相比，PASC-CVS患者的严重急性呼吸综合征-冠状病毒-2刺突蛋白S1的循环水平明显更高。此外，具有高血浆尖峰蛋白S1浓度的个体表现出升高的心率和正常的低频率，提示心脏β-肾上腺素能受体（β-AR）过度活跃。微尺度热电泳（MST）分析显示刺突蛋白与β1-和β2-AR结合，但不是D1-多巴胺受体。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分析显示，刺突蛋白与两个β-AR的胞外环2相互作用。在心肌细胞中，有或没有肾上腺素的情况下，刺突蛋白剂量依赖性地增加环磷酸腺苷的产生，表明其对β-ARs的变构效应。
结论：严重急性呼吸综合征-冠状病毒-2刺突蛋白作为变构β-AR激动剂，导致心脏β-AR多动症，从而有助于PASC-CVS。
结果：与非PASC-CVS患者和健康对照相比，PASC-CVS患者的严重急性呼吸综合征-冠状病毒-2刺突蛋白S1的循环水平明显更高。此外，具有高血浆尖峰蛋白S1浓度的个体表现出升高的心率和正常的低频率，提示心脏β-肾上腺素能受体（β-AR）过度活跃。微尺度热电泳（MST）分析显示刺突蛋白与β1-和β2-AR结合，但不是D1-多巴胺受体。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分析显示，刺突蛋白与两个β-AR的胞外环2相互作用。在心肌细胞中，有或没有肾上腺素的情况下，刺突蛋白剂量依赖性地增加环磷酸腺苷的产生，表明其对β-ARs的变构效应。
结论：严重急性呼吸综合征-冠状病毒-2刺突蛋白作为变构β-AR激动剂，导致心脏β-AR多动症，从而有助于PASC-CVS。
