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

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.

PTPN22 is a Potentially Diagnostic Biomarker for Abdominal Aortic Aneurysm

“…Moreover, PTPN22 showed interactions with 20 proteins/genes (Fig. S4e), among which 3 molecules have been reported to be important in AAA progress including PRKCD, EGFR, and PDGFRB [28][29][30]. Collective, these data highlight the important role of immune response and Garcinia acid as a potential therapeutic drugs for AAA.…”

Pharmacological Inhibition of Factor XIIa Attenuates Abdominal Aortic Aneurysm, Reduces Atherosclerosis, and Stabilizes Atherosclerotic Plaques

“…Upon histological examination of collagen deposition within AAAs, an indicator of structural stability, we observed a thick, fibrous layer of collagen deposited at the IMT–vessel interface in animals treated with 3F7. Recently, a study by Moran et al 32 investigated the gene and protein profiles of both an ApoE −/− FXII −/− double-knockout and an ApoE −/− 3F7-treated mouse model. The authors reported decreases in ADAM-17, endothelial growth factor receptor, and the matrix metalloproteinases MMP-2 and MMP-9 expression, 32 correlating to reduced local inflammation and remodeling, as well as to the preservation of extracellular matrix integrity.…”

Vitamin D deficiency promotes large rupture-prone abdominal aortic aneurysms and cholecalciferol supplementation limits progression of aneurysms in a mouse model

“…Both ultrasound and morphometric measurements have been found to have excellent inter-observer reproducibility in the investigators prior studies [11,14,15].…”

“…Maximum SRA diameter was measured using ultrasound as previously reported [14]. In study 2, the ultrasound was performed before the diet was introduced (baseline), before AngII infusion (day 0), and at day 14 and 28 after the AngII infusion was commenced.…”

“…Mice were then held in a dorsal position and scans were performed using a MyLab™ 70 VETXV platform (Esaote, Italy) with a 40 mm linear transducer at an operating frequency of 12 MHz (LA435; Esaote, Italy) to provide a sagittal image of the SRA. The maximum SRA diameter in the orthogonal plane was measured from outer wall to outer wall at peak systole using an inbuilt caliper feature [14,15].…”