Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice.

Corey S Moran,Erik Biros,Sai-Wang Seto,Jonathan Golledge,Con Panousis,Christoph Kleinschnitz,Susan K Morton,Smriti M Krishna

doi:10.1042/cs20191020

Abstract

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Chronic inflammation and excessive matrix remodelling are considered important in AAA pathogenesis. Kinins are bioactive peptides important in regulating inflammation. Stimulation of the kinin B2 receptor has been previously reported to promote AAA development and rupture in a mouse model. The endogenous B2 receptor agonist, bradykinin, is generated from the kallikrein-kinin system following activation of plasma kallikrein by Factor XII (FXII). In the current study whole-body FXII deletion, or neutralisation of activated FXII (FXIIa), inhibited expansion of the suprarenal aorta (SRA) of apolipoprotein E-deficient mice in response to angiotensin II (AngII) infusion. FXII deficiency or FXIIa neutralisation led to decreased aortic tumor necrosis factor-α-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-α-converting enzyme) (ADAM-17)) activity, plasma kallikrein concentration, and epithelial growth factor receptor (EGFR) phosphorylation compared with controls. FXII deficiency or neutralisation also reduced Akt1 and Erk1/2 phosphorylation and decreased expression and levels of active matrix metalloproteinase (Mmp)-2 and Mmp-9. The findings suggest that FXII, kallikrein, ADAM-17, and EGFR are important molecular mediators by which AngII induces aneurysm in apolipoprotein E-deficient mice. This could be a novel pathway to target in the design of drugs to limit AAA progression.

Highlights

Abdominal aortic aneurysm (AAA) is an important cause of death in older adults due to aortic rupture or complications of surgical repair [1]
The current study investigated the effect of Factor XII (FXII) deficiency and FXIIa neutralisation on the severity of aortic dilatation in apolipoprotein E-deficient (ApoE−/−) mice in response to angiotensin II (AngII)
Circulating and aortic levels of plasma kallikrein and bradykinin were determined in serum and suprarenal aorta (SRA) samples harvested from ApoE−/−FXII−/− mice, ApoE−/− mice administered the FXIIa-neutralising antibody 3F7 (10 mg/kg/48 h, i.p.) and ApoE−/− control mice

Summary

Introduction

Abdominal aortic aneurysm (AAA) is an important cause of death in older adults due to aortic rupture or complications of surgical repair [1]. The only treatment for AAA is surgical repair but previous clinical trials suggest this is not beneficial for small aneurysms or people that are deemed unfit [2,3]. A kinin-receptor antagonist limited aneurysm growth and reduced aortic rupture in the same experimental model [7]. These findings suggested that blocking kinin signalling could be a potential treatment strategy to limit AAA progression, how to achieve this most effectively and safely remained unclear

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Conclusion