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Title: Role of cyclo-oxygenase and related pathways in vascular health and disease
Author: Lundberg, Martina Helena
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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The cardioprotective hormone prostacyclin is a potent inhibitor of platelet activation and is produced in vascular endothelium by the concerted actions of cyclo-oxygenase and prostacyclin synthase. There is an ongoing, heated debate about which COX isoform (COX-1 or COX-2) regulates endothelial prostacyclin production. This is an important area of study since non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 selective inhibitors, used to treat arthritis, are associated with an increased risk of cardiovascular events, which has been linked to a reduction of urinary markers of prostacyclin. Thus, the aim of my thesis was to investigate the relative contribution of COX-1 versus COX-2 to endothelial prostacyclin production and vascular function. Using en face confocal imaging, I found that COX-1 immunoreactivity predominates over COX-2 in the endothelium of all blood vessels studied, including aortic arches from healthy wild type (WT, C57BL/6J) mice, in WT mice injected with endotoxin, ApoE-/- mice, rats with chronic heart failure and in human pulmonary artery. I have performed bioassays with blood vessels from WT versus COX-1-/- and COX-2-/- mice to show that COX-1 not COX-2 drives the majority of vascular prostacyclin production in both young (3 month old) and mature (12 month old) mice of both sexes. Phenotypic differences in the COX-1-/- and COX-2-/- mice included elevated levels of nuclear ‘primed’ NF-κB in the endothelium of both the protected (greater) and atherosclerosis-susceptible (lesser) curvature of the aortic arch. Despite COX-2-/- mice having normal endothelial prostacyclin production, more platelets adhered to the lesser curvature of the aortic arch. The techniques and validation protocols employed have shown COX-1 as the predominant endothelial COX isoform, responsible for vascular prostacyclin production. Low levels of constitutive COX-2 was found localised to susceptible areas of the vasculature where it may contribute to prostacyclin production on a local level to limit inflammation, atherosclerosis and platelet adhesion.
Supervisor: Mitchell, Jane ; Harrington, Louise Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available