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 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

There is no effect of TAFI inhibition of the growth of an established AAA in the Angiotensin II model.

<p>AAA were induced in hyperlipidaemic mice by infusion of Ang II 750 ng/kg/min. After 1 week, mice were treated with a single injection of either MA-TCK26D6 or NaCl control. AAA progression in both groups was evaluated at 2 weeks post injection using Vevo2100 pre-clinical ultrasound scanning, and 3D reconstructions of the aortic segment at risk of AAA formation were created. Panel A Aortic diameter, Panel B Aortic volume, Panel C The process of creating the 3D aortic reconstruction. Panel D Example 3D reconstruction showing AAA progression over time (0, 1 and 3 weeks post Angiotensin II infusion). Data is shown as mean±standard deviation.</p

AAA formation is altered in the presence of a TAFI-inhibitor.

<p>Mice were treated with saline control, NaCl 0.9%, (n = 23), Ang II (n = 35), Ang II and MA-TCK26D6 (n = 12) or Ang II and UK-396082 (n = 12) for 28 days. Panel A Incidence of AAA in each group. Panel B AAA size. Data is shown as mean±standard deviation. * p<0.05 compared to Angiotensin II alone by Chi-Squared testing.</p

The effect of TAFI inhibition on mortality in the Angiotensin II model of AAA.

<p>Panel A and B Blood pressure (BP) and heart rate (HR) measurements taken in all groups of mice in the second week of the experimental period using the CODA non-invasive BP device. Panel C and D Mortality of mice treated with Ang II, compared with NaCl 0.9% or Ang II plus MA-TCK26D6 or UK-396082. Data is shown as mean±standard deviation. Mortality in this model of AAA typically occurred early (Days 3–8 post initiation of Ang II infusion). * p<0.05 compared to Angiotensin II alone by Chi-Squared testing.</p

Aortic distensibility decreases with AAA formation, but is not affected by TAFI-inhibition, in the Angiotensin II model of AAA.

<p>The aorta was imaged in longitudinal section using the Vevo2100 scanner, and the distensibility measured using ECG-gated images and VevoVasc software. Panel A shows aortic wall distensibility in all mice with AAA (MA-TCK26D6 treated and sham treated). One week following initiation of Ang II infusion, mice received either MA-TCK26D6 or control (NaCl 0.9%) as an IV injection via the femoral vein. Panel B and C There was no difference in the change of distensibility by week 3 in mice receiving treatment with MA-TCK26D6 at 1 week compared with controls (data shown is change in distensibility between week 1 and week 3). Data is shown as mean±standard deviation, *** p = 0.001 compared to baseline by student t-test.</p