Studies into the Effects of Hypoxia on Matrix Metalloproteinases within the Abdominal Aortic Aneurysm

Abstract

Abdominal aortic aneurysm (AAA) is a permanent and irreversible localised dilation of the aortic wall which if left untreated can rupture leading to severe haemorrhage and death affecting over 5% of males over 50 years of age.The pathology of AAA is poorly understood, however research has shown that increased activity of matrix metalloproteinases (MMPs) leads to the destruction of major structural elements such as elastin and collagen within the aortic wall leading to weakening and resulting in aneurysm formation. Arterial wall hypoxia, which has been investigated in other pathological conditions may also play role in the pathogenesis of AAA. Research has also shown that hypoxia exists in vivo in the aneurysms of patients. This study has investigated the possible role of aortic wall hypoxia as a contributing factor for the increased expression of MMPs and also the affects if any on the endogenous inhibitors of MMPs known as TIMPs (tissue inhibitors of metalloproteinases). The major hypoxia transcription factor HIF-1α, along with Ets-1 and VEGF are also being investigated as mediating factors.Results demonstrated significant increases in expression of MMP-2 levels when human aortic smooth muscle cells were exposed to severe hypoxia over 48 hours. Increased levels of Tissue Inhibitor of Metalloproteinases (TIMPs) 1 and 2 were also noted in the HASMC supernatant of hypoxic VHASMC samples. Ets-1 and VEGF demonstrated raised levels in hypoxic HASMC whole cell lysate samples. Interestingly when HASMCS were treated with Bisphenol A (BpA) to inhibit the transcription factor HIF-1α during exposure to severe hypoxia, results showed an effect on the expression of MMP-2 levels in BpA treated hypoxic samples. Conclusions from this study could support a role for hypoxia and the involvment of HIF-1α in the signalling pathway.

Date of Award	1 Mar 2017
Original language	English
Awarding Institution	University of Bath
Supervisor	Vivienne Winrow (Supervisor) & Rex Tyrrell (Supervisor)