CYP2J2 Derived Eicosanoids and Endothelial Function

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DESCRIPTION (provided by applicant): Human cytochrome P450 2J2 (CYP2J2) oxidatively metabolizes arachidonic acid (AA) in endothelial cells to epoxyeicosatrienoic acids (EETs). The EETs possess potent vasodilatory and anti-inflammatory effects in the coronary microcirculation and peripheral vasculature, and may serve as an important reserve system to nitric oxide. However, the physiological functions of this pathway have not been well characterized in whole animal models or humans. Since impairment in the nitric oxide system is observed in patients with cardiovascular disease and "endothelial dysfunction" contributes significantly to disease pathogenesis, endothelial CYP2J2 activity may be clinically important. Single nucleotide polymorphisms in the gene encoding CYP2J2 have been identified recently, and may play an integral role in the development and progression of cardiovascular disease. In order to characterize the physiological functions of CYP2J2 in the vasculature, and evaluate the potential clinical importance of this metabolic pathway in patients with cardiovascular disease, this proposal aims to: (1) develop a transgenic mouse model with endothelial-specific overexpression of human CYP2J2 using the murine Tie2 promoter, (2) characterize the in vivo effects of constitutively increased, CYP2J2-mediated endothelial EET biosynthesis on the regulation of blood pressure and intravascular inflammation in these mice, and (3) determine if polymorphisms in the gene encoding CYP2J2 influence the development and/or progression of atherosclerotic disease in humans.