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

  • J Intern Med. 2024 Sep;296(3):291-297. doi: 10.1111/joim.20000.
Xiangning Deng  1  2  3  4  5 ,  Hongtu Cui  1  2  3  4  5 ,  Hao Liang  6 ,  Xinyu Wang  1  2  3  4  5 ,  Haiyi Yu  1  2  3  4  5 ,  Jingjia Wang  1  2  3  4  5 ,  Wenyao Wang  1  2  3  4  5 ,  Dongyang Liu  5  6 ,  Youyi Zhang  1  2  3  4  5 ,  Erdan Dong  1  2  3  4  7 ,  Yida Tang  1  2  3  4  5 ,  Han Xiao  1  2  3  4  5  7  8
Affiliations
  • 1. Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
  • 2. State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China.
  • 3. Haihe Laboratory of Cell Ecosystem, Beijing, China.
  • 4. Research Unit of Medical Science Research Management/Basic and Clinical Research of Metabolic Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, China.
  • 5. Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
  • 6. Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
  • 7. University of Health and Rehabilitation Sciences, Qingdao, China.
  • 8. Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi, China.
PMID: 39073192 DOI: 10.1111/joim.20000
Abstract

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.

Keywords
SARS‐CoV‐2 spike protein; agonist; cardiac sympathetic hyperactivity; long COVID; β‐adrenergic receptor.
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