Cargando…
Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms
OBJECTIVE: Thrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417566/ https://www.ncbi.nlm.nih.gov/pubmed/28472123 http://dx.doi.org/10.1371/journal.pone.0177117 |
_version_ | 1783233906620760064 |
---|---|
author | Bridge, Katherine Revill, Charlotte Macrae, Fraser Bailey, Marc Yuldasheva, Nadira Wheatcroft, Stephen Butlin, Roger Foster, Richard Scott, D. Julian Gils, Ann Ariёns, Robert |
author_facet | Bridge, Katherine Revill, Charlotte Macrae, Fraser Bailey, Marc Yuldasheva, Nadira Wheatcroft, Stephen Butlin, Roger Foster, Richard Scott, D. Julian Gils, Ann Ariёns, Robert |
author_sort | Bridge, Katherine |
collection | PubMed |
description | OBJECTIVE: Thrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition on AAA formation in adult ApoE-/- mice is unknown. The aim of this paper was to investigate the effects of TAFI inhibition on AAA development and progression. METHODS: Using the Angiotensin II model of AAA, male ApoE-/- mice were infused with Angiotensin II 750ng/kg/min with or without a monoclonal antibody inhibitor of plasmin-mediated activation of TAFI, MA-TCK26D6, or a competitive small molecule inhibitor of TAFI, UK-396082. RESULTS: Inhibition of TAFI in the Angiotensin II model resulted in a decrease in the mortality associated with AAA rupture (from 40.0% to 16.6% with MA-TCK26D6 (log-rank Mantel Cox test p = 0.16), and 8.3% with UK-396082 (log-rank Mantel Cox test p = 0.05)). Inhibition of plasmin-mediated TAFI activation reduced the incidence of AAA from 52.4% to 30.0%. However, late treatment with MA-TCK26D6 once AAA were already established had no effect on the progression of AAA in this model. CONCLUSIONS: The formation of intra-mural thrombus is responsible for the dissection and early rupture in the angiotensin II model of AAA, and this process can be prevented through inhibition of TAFI. Late treatment with a TAFI inhibitor does not prevent AAA progression. These data may indicate a role for inhibition of plasmin-mediated TAFI activation in the early stages of AAA development, but not in its progression. |
format | Online Article Text |
id | pubmed-5417566 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54175662017-05-14 Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms Bridge, Katherine Revill, Charlotte Macrae, Fraser Bailey, Marc Yuldasheva, Nadira Wheatcroft, Stephen Butlin, Roger Foster, Richard Scott, D. Julian Gils, Ann Ariёns, Robert PLoS One Research Article OBJECTIVE: Thrombin-activatable fibrinolysis inhibitor (TAFI) reduces the breakdown of fibrin clots through its action as an indirect inhibitor of plasmin. Studies in TAFI-deficient mice have implicated a potential role for TAFI in Abdominal Aortic Aneurysm (AAA) disease. The role of TAFI inhibition on AAA formation in adult ApoE-/- mice is unknown. The aim of this paper was to investigate the effects of TAFI inhibition on AAA development and progression. METHODS: Using the Angiotensin II model of AAA, male ApoE-/- mice were infused with Angiotensin II 750ng/kg/min with or without a monoclonal antibody inhibitor of plasmin-mediated activation of TAFI, MA-TCK26D6, or a competitive small molecule inhibitor of TAFI, UK-396082. RESULTS: Inhibition of TAFI in the Angiotensin II model resulted in a decrease in the mortality associated with AAA rupture (from 40.0% to 16.6% with MA-TCK26D6 (log-rank Mantel Cox test p = 0.16), and 8.3% with UK-396082 (log-rank Mantel Cox test p = 0.05)). Inhibition of plasmin-mediated TAFI activation reduced the incidence of AAA from 52.4% to 30.0%. However, late treatment with MA-TCK26D6 once AAA were already established had no effect on the progression of AAA in this model. CONCLUSIONS: The formation of intra-mural thrombus is responsible for the dissection and early rupture in the angiotensin II model of AAA, and this process can be prevented through inhibition of TAFI. Late treatment with a TAFI inhibitor does not prevent AAA progression. These data may indicate a role for inhibition of plasmin-mediated TAFI activation in the early stages of AAA development, but not in its progression. Public Library of Science 2017-05-04 /pmc/articles/PMC5417566/ /pubmed/28472123 http://dx.doi.org/10.1371/journal.pone.0177117 Text en © 2017 Bridge et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Bridge, Katherine Revill, Charlotte Macrae, Fraser Bailey, Marc Yuldasheva, Nadira Wheatcroft, Stephen Butlin, Roger Foster, Richard Scott, D. Julian Gils, Ann Ariёns, Robert Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms |
title | Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms |
title_full | Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms |
title_fullStr | Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms |
title_full_unstemmed | Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms |
title_short | Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms |
title_sort | inhibition of plasmin-mediated tafi activation may affect development but not progression of abdominal aortic aneurysms |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417566/ https://www.ncbi.nlm.nih.gov/pubmed/28472123 http://dx.doi.org/10.1371/journal.pone.0177117 |
work_keys_str_mv | AT bridgekatherine inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT revillcharlotte inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT macraefraser inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT baileymarc inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT yuldashevanadira inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT wheatcroftstephen inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT butlinroger inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT fosterrichard inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT scottdjulian inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT gilsann inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms AT ariënsrobert inhibitionofplasminmediatedtafiactivationmayaffectdevelopmentbutnotprogressionofabdominalaorticaneurysms |