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

Moran, Corey S., Seto, Sai-Wang, Biros, Erik, Krishna, Smriti M., Morton, Susan, Kleinschnitz, Christoph, Panousis, Con, and Golledge, Jonathan (2020) Factor XII blockade inhibits aortic dilatation in angiotensin II-infused apolipoprotein E-deficient mice. Clinical Science, 134 (9). pp. 1049-1061.

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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-alpha-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-alpha-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.

Item ID: 63498
Item Type: Article (Research - C1)
ISSN: 1470-8736
Keywords: a disintegrin and metalloproteinase-17; abdominal aortic aneurysm; epidermal growth factor receptor; factor xii; kallikreins; AAA
Copyright Information: © 2020 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
Funders: National Health and Medical Research Council of Australia (NHMRC), Queensland Government (QG), Cardiac Health Institute, Deutsche Forschungsgemeinschaft
Projects and Grants: NHMRC 1098717, NHMRC 1079369, QG SCRF, NHMRC 1117061
Date Deposited: 17 Jun 2020 07:41
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3201 Cardiovascular medicine and haematology > 320199 Cardiovascular medicine and haematology not elsewhere classified @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
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