Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms
| Autor: | Bridge, K, Revill, C, Macrae, F, Bailey, M, Yuldasheva, N, Wheatcroft, S, Butlin, R, Foster, R, Scott, DJ, Gils, A, Ariens, R |
|---|---|
| Přispěvatelé: | Hagemeyer, CE |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
Carboxypeptidase B2 Death Rates Immunology lcsh:Medicine Mouse Models macromolecular substances Pathology and Laboratory Medicine Research and Analysis Methods Biochemistry Vascular Medicine Mice Signs and Symptoms Model Organisms Apolipoproteins E Diagnostic Medicine Medicine and Health Sciences Animals Vascular Diseases Fibrinolysin cardiovascular diseases lcsh:Science Immune Response Blood Coagulation Aorta Demography Inflammation Mice Knockout Fibrin Fibrinolysis lcsh:R Biology and Life Sciences Proteins Animal Models Hematology Elastin Disease Models Animal Experimental Organism Systems People and Places Cardiovascular Anatomy Disease Progression cardiovascular system Blood Vessels lcsh:Q Anatomy Aneurysms Research Article Aortic Aneurysm Abdominal |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 5, p e0177117 (2017) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|