Linoleic acid is the most abundant polyunsaturated fatty acid in human adipose tissue, and it is readily oxidized by the liver and other organs. The applicant found that one oxidized derivative, 12,13-epoxy-9-keto-10-trans-octadecenoic acid, (""""""""EKODE""""""""), stimulates production of aldosterone by rat adrenal cells. EKODE circulates in mammalian blood, and plasma levels correlated with levels of aldosterone in 24 human subjects. In 12 African Americans in that cohort, EKODE levels also correlated with body mass index and systolic blood pressure. These observations suggest the hypothesis that EKODE is produced in the liver from linoleic acid, EKODE stimulates aldosterone secretion, and aldosterone and contributes to the hypertension and other sequelae of obesity. This pathogenesis may be particularly important in African Americans. Because its biosynthesis involves free radicals and oxygen, EKODE may be a product and hallmark of oxidative stress. The proposed experiments explore the relevance of EKODE in the regulation of aldosterone and blood pressure. The hypothesis will be addressed in three ways: by testing associations of EKODE with aldosterone and blood pressure in humans; by administering EKODE to animals and measuring their production of aldosterone and their blood pressure; and by devising ways to impair EKODE production. Two groups of 60 humans will be studied, both groups comprised of equal numbers of African Americans and Caucasians, males and females. Several measurements of body fat and blood pressure will be made, and blood and urine samples collected. All subjects will be studied while consuming carefully controlled diets. Measurements and sample collections will be done in clinical research units. Aldosterone and renin will be measured by radioimmunoassays, and EKODE by LC/MS. Statistical tests will be applied to see if EKODE levels correlate with aldosterone, obesity parameters, and/or blood pressure. One cohort will consume diets high and low in antioxidants to see if levels of EKODE, aldosterone, and blood pressure change together. EKODE will be administered to rats for two weeks by implanted osmotic minipumps. Urinary aldosterone will be measured. In rats receiving the optimum dose of EKODE, blood pressure will be measured by intraarterial catheterization. To identify non-toxic inhibitors of EKODE production, compounds will be screened in rat hepatocytes that convert labeled linoleic acid to EKODE. The proposed research is designed to explore the properties and relevance of the newly identified linoleic acid derivative EKODE with particular attention to aldosterone secretion and blood pressure. If dietary antioxidants reduce EKODE levels, or if non-toxic inhibitors of EKODE production are identified, it will be possible to test directly the role of EKODE in the hypertension of obesity and in other situations where aldosterone and oxidative stress are implicated.
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