The MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm disease
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 compo...
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ndltd-bl.uk-oai-ethos.bl.uk-6965692018-04-04T03:30:56ZThe MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm diseaseCrowther, Mathew1999Abdominal 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.616.1University of Leicesterhttp://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.696569http://hdl.handle.net/2381/29593Electronic Thesis or Dissertation |
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616.1 Crowther, Mathew The MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm disease |
description |
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. |
author |
Crowther, Mathew |
author_facet |
Crowther, Mathew |
author_sort |
Crowther, Mathew |
title |
The MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm disease |
title_short |
The MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm disease |
title_full |
The MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm disease |
title_fullStr |
The MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm disease |
title_full_unstemmed |
The MMP-2/MT1-MMP/TIMP-2 enzyme system in abdominal aortic aneurysm disease |
title_sort |
mmp-2/mt1-mmp/timp-2 enzyme system in abdominal aortic aneurysm disease |
publisher |
University of Leicester |
publishDate |
1999 |
url |
http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.696569 |
work_keys_str_mv |
AT crowthermathew themmp2mt1mmptimp2enzymesysteminabdominalaorticaneurysmdisease AT crowthermathew mmp2mt1mmptimp2enzymesysteminabdominalaorticaneurysmdisease |
_version_ |
1718619880026013696 |