Non-Cyclooxygenase Metabolism of Arachidonic Acid

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The studies of the Cyp2c epoxygenase and Cyp4a omega-hydroxylase branches of the cytochrome P450 (P450) arachidonic acid (AA) monooxygenase pathway have uncovered important functional roles for these enzymes in cell and organ physiology. Thus, the epoxy- and hydroxy-AA products of these enzymes (EETs and 20-HETE, respectively) participate in the regulation of renal transport and hemodynamics and thus, in the control and plasma salt and volume homeostasis. Mouse models of Cyp2c44 and Cyp4a10 dysfunction show a type of hypertension that is, as with prevalent forms of the human disease, sensitive to dietary salt intake, and linked to alterations in sodium transport. Genetic studies have uncovered associations between a variant of the human CYP4A11 gene and hypertension, and suggested a role for this 20-HETE synthase in the pathophysiology of salt sensitive hypertension. However, the site and mode of action of the P450 metabolites remains to be unequivocally defined, as it is their relevance to human hypertension and renal disease. Project #1, in conjunction with the functional components of the Program Project, will utilize molecular approaches for the characterization of mouse models of P450 isoform-dependent function and/or dysfunction, and for studies of the mechanisms of action their metabolites. Gene disruption and/or overexpression will be applied to studies of the physiological and/or pathophysiological role(s) of the Cyp2c44 epoxygenase and Cyp4a12 omega-hydroxylase. In collaborafion with Projects 2-5, we will use combinations of funcfional and biochemical approaches for: a) the analysis of P45b gene-dependent changes in AA metabolism and P450 isoform organ expression and regulation, and b) studies of the relevance of their human homologues to the pathophysiology of hypertension and renal disease. Our long term goals are to provide a molecular understanding of renal P450 eicosanoid biological significance and mode of action. The answers to these important quesfions are needed for the unequivocal definition of the physiological significance of these enzymes, their roles in human diseases such as hypertension, and for the development of rational strategies for future pharmacological and/or clinical intervention.