Inhibiting Wnt Signalling as a Strategy to Treat Abdominal Aortic Aneurysms

Abstract

ABSTRACT

Abdominal Aortic Aneurysms (AAAs) are the 10th leading cause of death in the UK with 6000 deaths reported each year. AAAs are caused by chronic inflammation, apoptosis of vascular smooth muscle cells and the loss of elastin and collagen. The loss of these key components leads to the bulging of the infrarenal aorta which can suddenly rupture and result death in 65-85% of patients. There is no medical treatment for patients with a detected AAA and are prescribed lifestyle changes until surgical intervention is required. Dysregulation of Wnt signalling has been implicated in cardiovascular diseases and is associated with inflammation, cell differentiation, migration, survival, and the upregulation of metalloproteinases.
Human control aortic tissue was compared to AAA tissue using immunohistochemistry. Significant increases in Porcupine protein, the Wnt co-receptor pLRP6, the active form of the canonical Wnt effector β-catenin, and the downstream canonical target gene Notum in AAAs indicated the activation of Wnt signalling in AAA disease.
Notum depalmitoylates Wnts thereby acting as an endogenous Wnt signalling inhibitor. Its role in cardiovascular disease pathology is relatively under-studied. To determine whether it may confer beneficial effects on the endothelium, human umbilical vein endothelial cells were agonized with tumour necrosis factor-α and treated with recombinant Notum. Notum successfully reduced THP-1 adhesions by 25% compared to control most likely through maintenance of PECAM-1 protein expression.
To determine the in-vivo effects of Wnt inhibition on AAAs, Apolipoprotein E-/- mice fed a high-fat diet were treated with Angiotensin II with or without a porcupine inhibitor for 30 days. The Porcupine inhibitor suppressed some of the detrimental Angiotensin II induced aortic remodelling effects by increasing elastin and glycoprotein concentration.
Taken together, Wnt inhibition may be a suitable medical intervention to treat AAAs as it will reduce Wnt signalling and endothelial inflammation while positively remodelling the aortic wall.

Date of Award	23 Jan 2024
Original language	English
Awarding Institution	University of Bristol
Sponsors	British Heart Foundation
Supervisor	Sarah J George (Supervisor) & Jason L Johnson (Supervisor)