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Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts
BACKGROUND: Angiotensin (ANG) II is involved in experimental hyperoxia-induced lung fibrosis. Angiotensin-converting enzyme-2 (ACE-2) degrades ANG II and is thus protective, but is downregulated in adult human and experimental lung fibrosis. Hyperoxia is a known cause of chronic fibrotic lung diseas...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119454/ https://www.ncbi.nlm.nih.gov/pubmed/25665060 http://dx.doi.org/10.1038/pr.2015.27 |
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author | Oarhe, Chinyere I. Dang, Vinh Dang, MyTrang Nguyen, Hang Gopallawa, Indiwari Gewolb, Ira H. Uhal, Bruce D. |
author_facet | Oarhe, Chinyere I. Dang, Vinh Dang, MyTrang Nguyen, Hang Gopallawa, Indiwari Gewolb, Ira H. Uhal, Bruce D. |
author_sort | Oarhe, Chinyere I. |
collection | PubMed |
description | BACKGROUND: Angiotensin (ANG) II is involved in experimental hyperoxia-induced lung fibrosis. Angiotensin-converting enzyme-2 (ACE-2) degrades ANG II and is thus protective, but is downregulated in adult human and experimental lung fibrosis. Hyperoxia is a known cause of chronic fibrotic lung disease in neonates, but the role of ACE-2 in neonatal lung fibrosis is unknown. We hypothesized that ACE-2 in human fetal lung cells might be downregulated by hyperoxic gas. METHODS: Fetal human lung fibroblast IMR90 cells were exposed to hyperoxic (95% O(2)/5% CO(2)) or normoxic (21% O(2)/5% CO(2)) gas in vitro. Cells and culture media were recovered separately for assays of ACE-2 enzymatic activity, mRNA, and immunoreactive protein. RESULTS: Hyperoxia decreased ACE-2 immunoreactive protein and enzyme activity in IMR90 cells (both P < 0.01), but did not change ACE-2 mRNA. ACE-2 protein was increased in the cell supernatant, suggesting protease-mediated ectodomain shedding. TAPI-2, an inhibitor of TNF-α−converting enzyme (TACE/ADAM17), prevented both the decrease in cellular ACE-2 and the increase in soluble ACE-2 (both P < 0.05). CONCLUSION: These data show that ACE-2 is expressed in fetal human lung fibroblasts but is significantly decreased by hyperoxic gas. They also suggest that hyperoxia decreases ACE-2 through a shedding mechanism mediated by ADAM17/TACE. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/pr.2015.27) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5119454 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-51194542016-11-22 Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts Oarhe, Chinyere I. Dang, Vinh Dang, MyTrang Nguyen, Hang Gopallawa, Indiwari Gewolb, Ira H. Uhal, Bruce D. Pediatr Res Article BACKGROUND: Angiotensin (ANG) II is involved in experimental hyperoxia-induced lung fibrosis. Angiotensin-converting enzyme-2 (ACE-2) degrades ANG II and is thus protective, but is downregulated in adult human and experimental lung fibrosis. Hyperoxia is a known cause of chronic fibrotic lung disease in neonates, but the role of ACE-2 in neonatal lung fibrosis is unknown. We hypothesized that ACE-2 in human fetal lung cells might be downregulated by hyperoxic gas. METHODS: Fetal human lung fibroblast IMR90 cells were exposed to hyperoxic (95% O(2)/5% CO(2)) or normoxic (21% O(2)/5% CO(2)) gas in vitro. Cells and culture media were recovered separately for assays of ACE-2 enzymatic activity, mRNA, and immunoreactive protein. RESULTS: Hyperoxia decreased ACE-2 immunoreactive protein and enzyme activity in IMR90 cells (both P < 0.01), but did not change ACE-2 mRNA. ACE-2 protein was increased in the cell supernatant, suggesting protease-mediated ectodomain shedding. TAPI-2, an inhibitor of TNF-α−converting enzyme (TACE/ADAM17), prevented both the decrease in cellular ACE-2 and the increase in soluble ACE-2 (both P < 0.05). CONCLUSION: These data show that ACE-2 is expressed in fetal human lung fibroblasts but is significantly decreased by hyperoxic gas. They also suggest that hyperoxia decreases ACE-2 through a shedding mechanism mediated by ADAM17/TACE. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/pr.2015.27) contains supplementary material, which is available to authorized users. Nature Publishing Group US 2015-02-09 2015 /pmc/articles/PMC5119454/ /pubmed/25665060 http://dx.doi.org/10.1038/pr.2015.27 Text en © International Pediatric Research Foundation, Inc. 2015 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. |
spellingShingle | Article Oarhe, Chinyere I. Dang, Vinh Dang, MyTrang Nguyen, Hang Gopallawa, Indiwari Gewolb, Ira H. Uhal, Bruce D. Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts |
title | Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts |
title_full | Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts |
title_fullStr | Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts |
title_full_unstemmed | Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts |
title_short | Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts |
title_sort | hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119454/ https://www.ncbi.nlm.nih.gov/pubmed/25665060 http://dx.doi.org/10.1038/pr.2015.27 |
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