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Title: Mechanisms of inflammatory endothelial dysfunction
Author: Clapp, Brian Richard
ISNI:       0000 0001 3552 024X
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2005
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Background: Inflammation is important in the development, progression and acute complications of atherosclerosis. Increased levels of inflammatory markers in humans predict the occurrence of future atherothrombotic events. Recognised risk factors for atherosclerosis have been shown to cause endothelial dysfunction, characterised by impaired endothelial nitric oxide-dependent vasodilator responses. Whether a similar mechanism underlies the effects of inflammation is not fully understood. This work explores this relationship, with a particular emphasis upon changes in the endothelial nitric oxide synthesis pathway. Methods: In vitro experiments were performed using organ bath pharmacology and western blotting to determine the effects of incubation of vascular tissue with high concentrations of the inflammatory marker C-reactive protein. An in vivo model of inflammation, using typhoid vaccination in healthy volunteers, was used to explore the time course of the vascular responses in comparison to the inflammatory markers. Further in vivo experiments involved selectively supplementing components of the nitric oxide pathway to determine if any were the cause of the endothelial dysfunction. Results: The work showed that acute inflammation caused transient endothelial dysfunction and that this was associated with increased oxidant stress. Supplementation experiments showed no substrate deficiency, rather that there was increased consumption of both nitric oxide and the co-factor tetrahydrobiopterin required for its production. In vitro and in vivo experiments indicated that, although C-reactive protein was a strong predictor of future events, it did not itself cause endothelial dysfunction, and in fact may be associated with an improvement in nitric oxide bioavailability through increased tetrahydrobiopterin. Conclusions: Overall, inflammation is associated with transient endothelial dysfunction and this may be important in the destabilisation of atherosclerotic disease and lead to clinical events. This change seems to be mediated by an increase in oxidant stress, which then has a number of related detrimental effects upon the nitric oxide pathway. However the acute phase marker, C-reactive protein, is only a marker of the underlying process and does not in itself appear to be causal in the development of endothelial abnormalities. Further work will be needed to more clearly characterise these effects and determine their clinical relevance.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available