Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706527
Title: Elevation of plasma high-density lipoproteins inhibits angiotensin II induced aortic aneurysm formation : investigating the mechanisms of action
Author: Huggins, Christopher
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2016
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
Abstract:
Abdominal Aortic Aneurysms (AAAs) are multi-genic, slow growing, degenerative vascular lesions resulting in focal aortic dilations. Following diagnosis, growth is monitored and the aneurysm surgically repaired when dilatation reaches 5.0 - 5.5 cm. Pharmacological treatments regressing or reducing growth rate remain a clinical ideal. Epidemiological evidence shows an inverse correlation between plasma High Density Lipoproteins (HDLs) and incidence of AAA, suggesting a role in the pathoaetiology This thesis investigates the role of HDLs in experimental AAA. Reconstituted HDL (rHDL - CSL-111) prevented AAA formation and reduced established AAA in mouse models. I used a hepatospecific adenoviral vector AdA-l; to induce production of human ApoA-l, increasing plasma HDL particles. Whilst infection with AdA-l significantly increased circulating human ApoA-l, it did not reduce established Ang Il-induced AAA or atheroma at the aortic root. Due to the complexity of HDL particles I elected to concentrate on mimicking its anti-inflammatory effects, rather than investigate alternate methods of increasing HDLs. One of HDL’s key anti-inflammatory effects is the prevention of Toll Like Receptor 4 (TLR4)-mediated inflammation, implicated in AAA development. I attempted to prevent AAA formation with a novel small molecule TLR4 antagonist, IAXO-102. IAXO-102 reduced TLR4-mediated aortic inflammation after three days of Ang II infusion; prevented AAA formation, and early rupture. Cytokines produced by TLR4-mediated inflammation stimulate other pro- inflammatory signalling pathways, such as the CD40/TRAF6 pathway. I investigated the effect of a CD40/TRAF6 inhibitor (687702), on experimental AAA. Following 3 days of Ang II infusion, treatment with Compound 6877002 made no significant difference to inflammatory markers associated with AAA; and no difference to vascular macrophage infiltration, a key cell mediator in AAA development. x HDLs are known to inhibit TLR4-mediated inflammation through up-regulation of Activating Transcription Factor 3 (ATF3), I investigated rHDLs manipulation of this negative feedback loop in HUVEC, and found stimulating HUVEC with rHDL, as well as with the TLR4 ligand LPS, induces ATF3 expression. Whilst surprisingly IAXO-102 did not prevent LPS stimulated ATF3 expression, 6877002 did, suggesting CD40/TRAF6 is essential for ATF3 expression. Through investigating the mechanisms in which HDL prevents AAA, I have highlighted the importance of TLR4 mediated inflammation in AAA and identified a potential pharmaceutical target.
Supervisor: Cockerill, Gillian ; Gaze, David ; Torsney, Evelyn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.706527  DOI: Not available
Share: