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Title: Effect of cigarette smoke on non-platelet thromboxane production
Author: Kakouros, Nikolaos
ISNI:       0000 0004 7972 0675
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2017
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Thromboxane A2 (TXA) generation in healthy adults is almost exclusively by platelets and suppressed by COX-1 inhibition using aspirin. In the RIGOR (Reduction in Graft Occlusion Rates) study, TXA production remained high in a group of patients with atheromatous disease after coronary artery bypass graft surgery (CABG) despite aspirin therapy and adequate platelet inhibition, suggesting a non-platelet source. We analysed data from 293 RIGOR study subjects to determine predictors of late-term outcomes after surgery and found non-platelet TXA to be an independent predictor of the composite endpoint of death, myocardial infarction, stroke and revascularization and an independent predictor of mortality. Multivariable modelling of 260 RIGOR subjects identified 8-isoprostaglandin F2o (8-iso-PGF2a), a potent vasoconstrictor generated non-enzymatically from arachidonic acid by oxidative stress, to be the strongest predictor of TXA levels 6 months after CABG. In these subjects, levels of urinary TXA and 8-iso-PGF2a were higher in smokers than non-smokers. Furthermore, TXA production from endothelial cells increased in response to 8-iso-PGF2a. We developed the use of aqueous cigarette smoke extract (CSE) as an in vitro model to study the effects of oxidative stress on TXA generation by endothelial cells (EC). Exposure of ECs to smoke led to increased 8-iso-PGF2aand TXA levels. CSE causes an increase in COX-2 mRNA and enzyme levels associated with increased intracellular oxidative stress. The effect of smoke on COX-2 is independent of NFkB activation, associated with an increase in COX-2 mRNA stability, but predominantly due to a p38 kinase-dependent upregulation of COX-2 transcriptome production. The effect leads to with increased endothelial production of thromboxane. In summary, our findings suggest non-platelet TXA production, resistant to aspirin therapy, is a novel risk factor for cardiovascular outcome and mortality. We demonstrate that dysfunctional endothelium, under oxidative stress, is a potential source of non-platelet TXA generation. We propose that reduction of non-platelet thromboxane production presents a novel potential therapeutic target for improving outcomes of patients with cardiovascular disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available