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Title: The role of hypoxia inducible factor-1 alpha (HIF-1*) in the pathogenesis of the abdominal aortic aneurysm (AAA)
Author: Erdozain, Olivia J.
ISNI:       0000 0001 3448 6713
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2008
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Abdominal aortic aneurysm (AAA) is a progressive and potentially fatal vascular disease that largely affects the male population >65 years of age. Gradual weakening of the aortic wall by matrix degrading factors, and consequential widening and dilation, reduce its integrity increasing the probability of eventual rupture. The aetiology and pathogenesis are largely unknown. Matrix metalloproteinases (MMPs) are largely responsible for the initial elastin and eventual collagen destruction (Freestone et al., 1995; Crowther et al., 2000 & 2000a). Aortic wall pOz is reduced possibly due to intraluminal thrombus which suggests reactive oxygen species involvement (Vorp et al., 1998 & 2001). Elective AM (>5cm) repair has provided researchers with tissue in the latter stages of pathogenesis, however it is the precise early signal transduction cascade that must be evaluated in order for early pharmacological intervention to exclude the need for expensive and risky surgical intervention. Experimentation herein addresses the hypothesis that HIF-1a andlor Ets-1 as a function of hypoxia initiate the matrix destruction that facilitates AAA formation. In order to fully elucidate the very small/premature/precluding AAA in the absence of AAA tissues of this type and in an attempt to mimic the AM development models, AAA specimens were dissected into three different regions according to the anatomical structure. The hypothesis was made that the most dilated or 'body' region of the particular AAA represented the most advanced stage of that AAA pathology. Conversely the 'proximal' and 'distal' regions would represent a more naive/earlyAM pathology. Qualitative and quantitative analysis of the AAA wall was carried out using various experimental techniques. Immunohistochemistry, gelatin zymography, RT-PCR and PCR served as appropriate methodologies to evaluate the secreted and internalised MMP factors (MMP-1, MT-MMP-1, MMP2, MMP-3, MMP-7, MMP-9, TIMP-1) for the different AM sac regions. Cell and tissue culture in normoxic and hypoxic (5%, 3%, 2% & 1% O2) environments were conducted in parallel to assess potential differences between secreted and internalised MMP factors. Hypoxia of the aorta, Hypoxia Inducible Factor-1 alpha (HIF-1a) and E26 transforming specific-1 (Ets-1) signalling transcription factor presence in AAA were evaluated using Immunohistochemistry, double immunofluorescence and PCR. Comparative analysis was performed between normal aorta and MA. Ulcerated and smooth carotid tissues obtained during endarterectomy from asymptomatic and symptomatic patients were also evaluated for MMP and HIF-1a differences and compared toMAtissues. Significant differences were noted between the MA regions for MMP presence. HIF-1a and Ets-1 immunopositivity was noted for all MAregions but predominated in the body region. Significant differences were noted between MA and normal aorta for MMPs and hypoxic factors. Vascular smooth muscle cells exposed to decreasing 02 tensions showed significant differences for secreted MMPs and MMP mRNA. Significantly different MMP expression was observed between smooth and ulcerated carotid plaques. In addition, symptomatic and asymptomatic carotid plaques display different HIF-1a status. In conclusion the combined results of the 5 experimental chapters provide compelling evidence that hypoxia facilitates up-regulation of MMPs in VSMCs and that HIF-1a and Ets-1 inhibition in the early stages of AAA pathogenesis could potentially avert further matrix degradation. Screening for HIF-1a in the carotid stenosis patient might provide a better insight into symptomology status. Likewise, screening for HIF-1a and Ets-1 elevations in the aorta might be predictive of earlyMAdevelopment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available