GENETIC POLYMORPHISMS IN THE EPOXYGENASE PATHWAY IN HYPERTENSION

$0P20FY2002RRNIH

Tulane University Of Louisiana, New Orleans LA

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Abstract

Vasoactive arachidonic acid metabolites of the cytochrome P450 (CYP) epoxygenase pathway, the epoxides, have been implicated in animal and human studies of hypertension. The epoxide 11-12 epieicosatrienoic acid (11,12-EET), the putative endothelium derived hyperpolarizing factor (EDHF)is formed by the enzymes CYP2C9, CYP2C8, and converted to its corresponding dihydroxy metabolite (DHET) by soluble epoxide hydrolase (sEH). CYP2C9 and CYP2C8 and sEH exhibit a high prevalence of genetic polymorphisms which may lead to altered levels of epoxides and reduced formation of EDRH in hypertensive patients. The perturbed vasoactive epoxide profile produced by genetic polymorphisms in this pathway may play a mechanistic role in a subgroup of patients with hypertension. Specific Aim 1: We propose to determine the prevalence of CYP2C9fC8 and sEH polymorphisms in hypertensive populations including both African Americans and Caucasians and compare these to the prevalence of these polymorphisms in race matched healthy control subjects. Specific Aim 2: We will also measure levels of EETs and DHETs in plasma and urine of patients with hypertension compared to race matched healthy controls for the various genotypes of CYP2C8/C9 and sEH. Specific Aim 3: We will determine whether in vivo CYP2C9 activity as measured by plasma S/R warfarin ratio, correlates with plasma and urine concentrations of eicosanoid metabolites for the various CYP2C9 genotypes in these same groups. Specific Aim 4: We will determine brachial artery reactivity via ultrasound in each of these same genotypic subgroups in race matched hypertensives and controls. The results from these studies will lead to new insights into the role of polymorphisms of the P450 epoxygenase system in cardiovascular regulation. The studies may demonstrate a role of these polymorphisms in some hypertensive populations, but in any case will provide increased understanding of the role of EETs and DHETs in vascular reactivity and blood pressure regulation.

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