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ADAM-17 Activity and Its Relation to ACE2 : Implications for Severe COVID-19

Sun, Jiangming LU orcid ; Edsfeldt, Andreas LU ; Svensson, Joel LU ; Ruge, Toralph LU ; Goncalves, Isabel LU orcid and Swärd, Per LU (2024) In International Journal of Molecular Sciences 25(11).
Abstract

There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between... (More)

There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate ADAM-17 and ACE2 gene expressions by age and sex in ages between 20–80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity (p = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance (p = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of ADAM-17 to ACE2 gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin–angiotensin system (RAS) and immune signaling. Additionally, differences in ACE2 and ADAM-17 gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
a disintegrin and metalloproteinase-17, angiotensin-converting enzyme 2, coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2
in
International Journal of Molecular Sciences
volume
25
issue
11
article number
5911
publisher
MDPI AG
external identifiers
  • scopus:85195883992
ISSN
1661-6596
DOI
10.3390/ijms25115911
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024 by the authors.
id
42d66c53-6955-48d3-ad56-f359fcc21526
date added to LUP
2024-07-25 12:43:28
date last changed
2024-07-25 12:44:36
@article{42d66c53-6955-48d3-ad56-f359fcc21526,
  abstract     = {{<p>There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate ADAM-17 and ACE2 gene expressions by age and sex in ages between 20–80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity (p = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance (p = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of ADAM-17 to ACE2 gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin–angiotensin system (RAS) and immune signaling. Additionally, differences in ACE2 and ADAM-17 gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies.</p>}},
  author       = {{Sun, Jiangming and Edsfeldt, Andreas and Svensson, Joel and Ruge, Toralph and Goncalves, Isabel and Swärd, Per}},
  issn         = {{1661-6596}},
  keywords     = {{a disintegrin and metalloproteinase-17; angiotensin-converting enzyme 2; coronavirus disease 2019; severe acute respiratory syndrome coronavirus 2}},
  language     = {{eng}},
  number       = {{11}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{ADAM-17 Activity and Its Relation to ACE2 : Implications for Severe COVID-19}},
  url          = {{http://dx.doi.org/10.3390/ijms25115911}},
  doi          = {{10.3390/ijms25115911}},
  volume       = {{25}},
  year         = {{2024}},
}