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.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:706527 |
| Date | January 2016 |
| Creators | Huggins, Christopher |
| Contributors | Cockerill, Gillian ; Gaze, David ; Torsney, Evelyn |
| Publisher | St George's, University of London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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