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Aneurysm severity is suppressed by deletion of CCN4
Patients with abdominal aortic aneurysms are frequently treated with high-risk surgery. A pharmaceutical treatment to reverse aneurysm progression could prevent the need for surgery and save both lives and healthcare resources. Since CCN4 regulates cell migration, proliferation and apoptosis, proces...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222476/ https://www.ncbi.nlm.nih.gov/pubmed/34080128 http://dx.doi.org/10.1007/s12079-021-00623-5 |
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author | Williams, Helen Wadey, Kerry S. Frankow, Aleksandra Blythe, Hazel C. Forbes, Tessa Johnson, Jason L. George, Sarah J. |
author_facet | Williams, Helen Wadey, Kerry S. Frankow, Aleksandra Blythe, Hazel C. Forbes, Tessa Johnson, Jason L. George, Sarah J. |
author_sort | Williams, Helen |
collection | PubMed |
description | Patients with abdominal aortic aneurysms are frequently treated with high-risk surgery. A pharmaceutical treatment to reverse aneurysm progression could prevent the need for surgery and save both lives and healthcare resources. Since CCN4 regulates cell migration, proliferation and apoptosis, processes involved in aneurysm progression, it is a potential regulator of aneurysm progression. We investigated the role of CCN4 in a mouse aneurysm model, using apolipoprotein-E knockout (ApoE(−/−)) mice fed high fat diet and infused with Angiotensin II (AngII). Blood pressure was similarly elevated in CCN4(−/−)ApoE(−/−) mice and CCN4(+/+)ApoE(−/−) mice (controls) in response to AngII infusion. Deletion of CCN4 significantly reduced the number of ruptured aortae, both thoracic and abdominal aortic area, and aneurysm grade score, compared to controls. Additionally, the frequency of vessel wall remodelling and the number of elastic lamina breaks was significantly suppressed in CCN4(−/−)ApoE(−/−) mice compared to controls. Immunohistochemistry revealed a significantly lower proportion of macrophages, while the proportion of smooth muscle cells was not affected by the deletion of CCN4. There was also a reduction in both proliferation and apoptosis in CCN4(−/−)ApoE(−/−) mice compared to controls. In vitro studies showed that CCN4 significantly increased monocyte adhesion beyond that seen with TNFα and stimulated macrophage migration by more than threefold. In summary, absence of CCN4 reduced aneurysm severity and improved aortic integrity, which may be the result of reduced macrophage infiltration and cell apoptosis. Inhibition of CCN4 could offer a potential therapeutic approach for the treatment of aneurysms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12079-021-00623-5. |
format | Online Article Text |
id | pubmed-8222476 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-82224762021-07-09 Aneurysm severity is suppressed by deletion of CCN4 Williams, Helen Wadey, Kerry S. Frankow, Aleksandra Blythe, Hazel C. Forbes, Tessa Johnson, Jason L. George, Sarah J. J Cell Commun Signal Research Article Patients with abdominal aortic aneurysms are frequently treated with high-risk surgery. A pharmaceutical treatment to reverse aneurysm progression could prevent the need for surgery and save both lives and healthcare resources. Since CCN4 regulates cell migration, proliferation and apoptosis, processes involved in aneurysm progression, it is a potential regulator of aneurysm progression. We investigated the role of CCN4 in a mouse aneurysm model, using apolipoprotein-E knockout (ApoE(−/−)) mice fed high fat diet and infused with Angiotensin II (AngII). Blood pressure was similarly elevated in CCN4(−/−)ApoE(−/−) mice and CCN4(+/+)ApoE(−/−) mice (controls) in response to AngII infusion. Deletion of CCN4 significantly reduced the number of ruptured aortae, both thoracic and abdominal aortic area, and aneurysm grade score, compared to controls. Additionally, the frequency of vessel wall remodelling and the number of elastic lamina breaks was significantly suppressed in CCN4(−/−)ApoE(−/−) mice compared to controls. Immunohistochemistry revealed a significantly lower proportion of macrophages, while the proportion of smooth muscle cells was not affected by the deletion of CCN4. There was also a reduction in both proliferation and apoptosis in CCN4(−/−)ApoE(−/−) mice compared to controls. In vitro studies showed that CCN4 significantly increased monocyte adhesion beyond that seen with TNFα and stimulated macrophage migration by more than threefold. In summary, absence of CCN4 reduced aneurysm severity and improved aortic integrity, which may be the result of reduced macrophage infiltration and cell apoptosis. Inhibition of CCN4 could offer a potential therapeutic approach for the treatment of aneurysms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12079-021-00623-5. Springer Netherlands 2021-06-02 2021-09 /pmc/articles/PMC8222476/ /pubmed/34080128 http://dx.doi.org/10.1007/s12079-021-00623-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Williams, Helen Wadey, Kerry S. Frankow, Aleksandra Blythe, Hazel C. Forbes, Tessa Johnson, Jason L. George, Sarah J. Aneurysm severity is suppressed by deletion of CCN4 |
title | Aneurysm severity is suppressed by deletion of CCN4 |
title_full | Aneurysm severity is suppressed by deletion of CCN4 |
title_fullStr | Aneurysm severity is suppressed by deletion of CCN4 |
title_full_unstemmed | Aneurysm severity is suppressed by deletion of CCN4 |
title_short | Aneurysm severity is suppressed by deletion of CCN4 |
title_sort | aneurysm severity is suppressed by deletion of ccn4 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222476/ https://www.ncbi.nlm.nih.gov/pubmed/34080128 http://dx.doi.org/10.1007/s12079-021-00623-5 |
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