Characterization And Functional Significance Of P450 Ara

Environmental Health Sciences

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Abstract

Cytochromes P450 metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids (EETs) which have potent effects on cardiovascular function. Current research involves: (1) characterization of CYP2J subfamily P450s at the biochemical/molecular levels; (2) evaluation of the functional roles of CYP2J products in cardiovascular cell/organ physiology; and (3) examination of this pathway in selected animal models of human disease (ischemic heart disease, hypertension, atherosclerosis). We have discovered a number of mammalian CYP2Js, although we have focused most of our efforts on human CYP2J2. Human CYP2J2 is the major human P450 expressed in heart and vasculature, where it is localized to cardiac myocytes and endothelial cells, and is active in the metabolism of AA to EETs. CYP2J2-derived EETs inhibit cytokine-induced endothelial cell adhesion molecule expression and leukocyte adhesion to the vascular wall via a mechanism that involves inhibition of I B kinase and NF B. CYP2J2-derived EETs also induce tissue plasminogen activator (t-PA) gene expression via a mechanism that involves activation of G s and increased cAMP. These findings indicate that EETs possess both antiinflammatory and fibrinolytic properties within the vasculature. Exposure of endothelial cells to hypoxia-reoxygenation (H-R) decreases CYP2J2 protein expression. Transfection of endothelial cells with the CYP2J2 cDNA attenuates H-R-induced endothelial injury via both EET-dependent and antioxidant mechanisms. CYP2J2 transgenic mice were developed to study the effects of increased EETs on cardiovascular function in vivo. These mice have normal basal heart function, improved post-ischemic left ventricular functional recovery, prolonged cardiac action potential duration, and exhibit enhanced beta-adrenergic receptor responsiveness. We have bred these mice into an ApoE-/- background to examine the effects of CYP2J2 overexpression on the development of atherosclerosis. The human CYP2J2 gene has been cloned, sequenced and characterized. We have identified several rare but functionally relevant CYP2J2 polymorphic variants that have reduced arachidonic acid metabolic capacity. We are currently examining whether any of these variants are present at higher frequency in patients with cardiovascular disease and hypertension vs. normals.