U124015.pdf (21.63 MB)
Download file

The MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm disease

Download (21.63 MB)
thesis
posted on 15.12.2014, 10:31 authored by Mathew. Crowther
Abdominal aortic aneurysm (AAA) represents a complex biochemical pathology, characterised by marked tissue remodelling and severe inflammation. The weakening of the arterial wall is assessed with elevated production of matrix metalloproteinases (MMPs), enzymes that degrade extracellular matrix components causing a reduction in tensile strength and mechanical integrity. However, the cause of this overproduction of MMPs remains poorly understood.;Analysis of small AAAs has demonstrated that MMP-2 is the most prominent MMP, an enzyme known to be produced by most mesenchymal cells. The present thesis investigated the hypothesis that aortic smooth muscle cells (SMCs) are the source of excess MMP-2, which may degrade elastin fibres and initiate the degenerative and inflammatory process characteristic of aneurysmal disease.;Histological analysis of control and aneurysm tissue was followed by focused testing of the hypothesis, by isolating and comparing SMCs from control and aneurysmal aortas. Aneurysmal SMCs expressed significantly more MMP-2 than control cells, but levels of MT1-MMP and TIMP-2 were not significantly different. MMP-2 was shown to be capable of inducing elastolytic changes characterise of aneurysm disease in a porcine in vitro model of AAA.;Similar methods suggested that this was not the case in dermal fibroblasts, providing evidence that the elevated level of MMP-2 in SMCs was not reflected in all mesenchyme-derived tissues. Published evidence suggested that AAA may be a local manifestation of a generalised dilating process, and this hypothesis was addressed by examining the MMP expression of vascular tissue remote from the aneurysm site. Inferior mesenteric vein from AAA patients produced elevated levels of MMP-2 compared to control vein, suggesting that this phenomenon may be systemic but vascular tissue-specific in nature. These data suggest that AAA patients may be predisposed to vascular elastolysis, manifesting itself in later life as aneurysmal dilatation of the aorta. In conclusion, a novel model of AAA aetiology is proposed.

History

Date of award

01/01/1999

Author affiliation

Medicine

Awarding institution

University of Leicester

Qualification level

Doctoral

Qualification name

PhD

Language

en

Usage metrics

Categories

Keywords

Exports