Collections > Electronic Theses and Dissertations > Cytochrome P450 Derived Eicosanoids, Endothelial Function and Cardiovascular Disease
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Endothelial dysfunction plays an integral role in the pathogenesis and progression of cardiovascular disease in humans. The development of endothelial dysfunction has been primarily ascribed to functional impairments in nitric oxide biosynthesis. However, arachidonic acid metabolism by the cyclooxygenase and cytochrome P450 epoxygenase pathways also appears to regulate endothelial function. Consequently, genetic variation in these pathways may be important modifiers of cardiovascular disease risk in humans. The collective objective of the studies outlined in this doctoral dissertation was to determine if genetic variation in these established (NOS3, PTGS1 and PTGS2) and recently characterized (EPHX2, CYP2J2 and CYP2C8) pathways are significantly associated with cardiovascular disease risk. First, metabolic studies conducted in vitro demonstrate that certain genetic variants in cyclooxygenase-1 possess significantly lower metabolic activity compared to wild-type cyclooxygenase-1. Second, the observed associations between genetic variation in PTGS1, PTGS2 and NOS3 and risk of incident coronary heart disease and ischemic stroke events further implicate these established pathways in the development of cardiovascular disease in humans. Third, the observed associations between genetic variation in EPHX2, CYP2J2 and CYP2C8 and risk of incident coronary heart disease events also demonstrate the potential importance of the cytochrome P450 epoxygenase pathway in the pathogenesis of ischemic cardiovascular disease in humans. Fourth, the development and baseline characterization of transgenic mice that exhibit vascular endothelial cell-specific overexpression of either human CYP2J2 or CYP2C8 will enable further mechanistic characterization of the cytochrome P450 epoxygenase pathway in the regulation of endothelial function and the pathogenesis of cardiovascular disease.