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COVID-19 and nicotine as a mediator of ACE-2

Janice M. Leung, Chen Xi Yang, Don D. Sin
European Respiratory Journal 2020 55: 2001261; DOI: 10.1183/13993003.01261-2020
Janice M. Leung
1Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada
2Division of Respiratory Medicine, Dept of Medicine, St. Paul's Hospital, Vancouver, BC, Canada
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Chen Xi Yang
1Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada
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Don D. Sin
1Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada
2Division of Respiratory Medicine, Dept of Medicine, St. Paul's Hospital, Vancouver, BC, Canada
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  • For correspondence: Don.Sin@hli.ubc.ca
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Abstract

α7-nAChR may upregulate ACE-2 https://bit.ly/2xS0cfT

From the authors:

We recently reported that current smokers and those with COPD had higher airway epithelial cell expression of the angiotensin-converting enzyme II (ACE-2) viral entry receptor [1]. We thus read with great interest the work of P. Russo and co-workers, which proposes a mechanism for this finding, namely that this upregulation is mediated by nicotine exposure specifically through the α7 subtype of nicotine acetylcholine receptors (α7-nAChR). While exposure to increasing concentrations of nicotine caused epithelial cells to increase ACE-2 levels, subsequent gene silencing of α7-nAChR appeared to significantly dampen this response. A secondary transcriptome sequencing analysis of our cohort (consisting of 42 subjects who underwent bronchoscopy for epithelial cell brushings [1]) reveals evidence in support of this hypothesis. We found that airway epithelial cell expression of CHRNA7, encoding α7-nAChR, was significantly correlated with the expression of ACE2 (Pearson r=0.54, p=2.31×10−8) (figure 1). There was significantly higher CHRNA7 expression in those with COPD (2.75±0.73 versus 2.14±0.43 in those without COPD; p=1.47×10−4), with a trend towards higher expression in current smokers compared to former and never smokers (2.86±0.92 in current smokers, 2.35±0.57 in former smokers, and 2.27±0.45 in never smokers; p=6.16×10−2). CHRNA7 was also negatively correlated with forced expiratory volume in 1 s percent predicted (Pearson r=−0.37, p=2.83×10−4). Interestingly, CHRNA7 was positively if weakly correlated with body mass index (Pearson r=0.14, p=6.31×10−3), raising the intriguing possibility that nicotine receptor mediation of ACE-2 may also be related to why obese individuals have made up a considerable proportion of coronavirus disease 2019 (COVID-19) cases [2].

FIGURE 1
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FIGURE 1

Transcriptome profiles generated through RNA-Seq of airway epithelial cells demonstrated a significant positive correlation between ACE2 and CHRNA7 expression.

Together, these data further help to characterise the connections between airway epithelial ACE-2, and α7-nAChR, and the unique vulnerability of patients with COPD to severe COVID-19. α7-nAChR's widespread abundance in the human body, from neuronal tissue to immune cells to the lung and digestive tract, and its various roles in diseases such as schizophrenia [3], Alzheimer's disease [4] and Parkinson's disease [5] has meant that considerable work has already been done to target α7-nAChR as a therapeutic modality. As an example, α7-nAChR antagonists for the purpose of smoking cessation have long been proposed [6] and the idea of potentially repurposing these compounds for a pandemic with few therapeutic options currently available is certainly appealing. Whether α7-nAChR-selective antagonists, such as methyllycaconitine [7] and α-conotoxin [8], can meaningfully alter ACE-2 expression to prevent severe acute respiratory syndrome coronavirus 2 entry into the airway epithelium seems the next logical investigation in our furious pursuit for better therapeutics.

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Footnotes

  • Conflict of interest: J.M. Leung has nothing to disclose.

  • Conflict of interest: C.X. Yang has nothing to disclose.

  • Conflict of interest: D.D. Sin reports grants from Merck, personal fees for advisory board work from Sanofi-Aventis and Regeneron, grants and personal fees for lectures from Boehringer Ingelheim and AstraZeneca, personal fees for lectures and advisory board worm from Novartis, outside the submitted work.

  • Received April 18, 2020.
  • Accepted April 20, 2020.
  • Copyright ©ERS 2020
http://creativecommons.org/licenses/by-nc/4.0/

This version is distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

References

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    ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. Eur Respir J 2020; 55: 2000688. doi:10.1183/13993003.00688-2020
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    Linkage disequilibrium for schizophrenia at the chromosome 15q13-14 locus of the alpha7-nicotinic acetylcholine receptor subunit gene (CHRNA7). Am J Med Genet 2001; 105: 20–22. doi:10.1002/1096-8628(20010108)105:1<20::AID-AJMG1047>3.0.CO;2-C
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    Dimerization of alpha-conotoxins as a strategy to enhance the inhibition of the human alpha7 and alpha9alpha10 nicotinic acetylcholine receptors. J Med Chem 2020; 63: 2974–2985. doi:10.1021/acs.jmedchem.9b01536
    OpenUrl
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COVID-19 and nicotine as a mediator of ACE-2
Janice M. Leung, Chen Xi Yang, Don D. Sin
European Respiratory Journal Jun 2020, 55 (6) 2001261; DOI: 10.1183/13993003.01261-2020

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COVID-19 and nicotine as a mediator of ACE-2
Janice M. Leung, Chen Xi Yang, Don D. Sin
European Respiratory Journal Jun 2020, 55 (6) 2001261; DOI: 10.1183/13993003.01261-2020
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