Inhibition of plasmin-mediated TAFI activation may affect development but not progression of abdominal aortic aneurysms.

Abstract

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.

• Authors: Katherine Bridge, Charlotte Revill, Fraser Macrae, Marc Bailey, Nadira Yuldasheva, Stephen Wheatcroft, Roger Butlin, Richard Foster, D Julian Scott, Ann Gils, Robert Ariens
• Journal: PloS one (PLoS One) Vol. 12 Issue 5 Pg. e0177117 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28472123 (Publication Type: Journal Article)

Chemical References

• Apolipoproteins E
• Carboxypeptidase B2
• Cpb2 protein, mouse
• Fibrinolysin

Topics

• Animals
• Aortic Aneurysm, Abdominal (pathology)
• Apolipoproteins E (genetics)
• Carboxypeptidase B2 (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Disease Progression
• Fibrinolysin (metabolism)
• Male
• Mice
• Mice, Knockout