ADAM-17 Activity and Its Relation to ACE2 : Implications for Severe COVID-19
(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.
(Less)
- author
- Sun, Jiangming
LU
; Edsfeldt, Andreas LU ; Svensson, Joel LU ; Ruge, Toralph LU ; Goncalves, Isabel LU
and Swärd, Per LU
- organization
-
- Cardiovascular Research - Translational Studies (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- Diabetes - Molecular Metabolism (research group)
- Malaria and Babesia (research group)
- Clinical Chemistry, Malmö (research group)
- Cardiovascular Research - Hypertension (research group)
- EpiHealth: Epidemiology for Health
- publishing date
- 2024-06
- 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}}, }