© 2000 American Heart Association, Inc.
Molecular Medicine |
Soluble Epoxide Hydrolase Regulates Hydrolysis of Vasoactive Epoxyeicosatrienoic Acids
From the Department of Biopharmaceutical Sciences (Z.Y., F.X., L.M.H., D.L.K.), School of Pharmacy, and Department of Physiological Nursing (M.M.E.), School of Nursing, University of California, San Francisco, Calif; Department of Entomology (C.M., A.J.D., J.W.N., B.D.H.), University of California, Davis, Calif; and the Division of Intramural Research (C.P., L.G., D.C.Z.), National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
Correspondence to Deanna L. Kroetz, PhD, Department of Biopharmaceutical Sciences, 513 Parnassus Box 0446, San Francisco, CA 94143-0446. E-mail deanna{at}itsa.ucsf.edu
Abstract—The cytochrome P450-derived epoxyeicosatrienoic acids (EETs) have potent effects on renal vascular reactivity and tubular sodium and water transport; however, the role of these eicosanoids in the pathogenesis of hypertension is controversial. The current study examined the hydrolysis of the EETs to the corresponding dihydroxyeicosatrienoic acids (DHETs) as a mechanism for regulation of EET activity and blood pressure. EET hydrolysis was increased 5- to 54-fold in renal cortical S9 fractions from the spontaneously hypertensive rat (SHR) relative to the normotensive Wistar-Kyoto (WKY) rat. This increase was most significant for the 14,15-EET regioisomer, and there was a clear preference for hydrolysis of 14,15-EET over the 8,9- and 11,12-EETs. Increased EET hydrolysis was consistent with increased expression of soluble epoxide hydrolase (sEH) in the SHR renal microsomes and cytosol relative to the WKY samples. The urinary excretion of 14,15-DHET was 2.6-fold higher in the SHR than in the WKY rat, confirming increased EET hydrolysis in the SHR in vivo. Blood pressure was decreased 22±4 mm Hg (P<0.01) 6 hours after treatment of SHRs with the selective sEH inhibitor N,N'-dicyclohexylurea; this treatment had no effect on blood pressure in the WKY rat. These studies identify sEH as a novel therapeutic target for control of blood pressure. The identification of a potent and selective inhibitor of EET hydrolysis will be invaluable in separating the vascular effects of the EET and DHET eicosanoids.
Key Words: epoxyeicosatrienoic acids • dihydroxyeicosatrienoic acids • cytochrome P450 • soluble epoxide hydrolase • hypertension
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B. Yang, L. Graham, S. Dikalov, R. P. Mason, J. R. Falck, J. K. Liao, and D. C. Zeldin Overexpression of Cytochrome P450 CYP2J2 Protects against Hypoxia-Reoxygenation Injury in Cultured Bovine Aortic Endothelial Cells Mol. Pharmacol., August 1, 2001; 60(2): 310 - 320. [Abstract] [Full Text] [PDF]
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 I. Fleming and R. Busse Vascular cytochrome P450 in the regulation of renal function and vascular tone: EDHF, superoxide anions and blood pressure Nephrol. Dial. Transplant., July 1, 2001; 16(7): 1309 - 1311. [Full Text] [PDF]
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X. Fang, T. L. Kaduce, N. L. Weintraub, S. Harmon, L. M. Teesch, C. Morisseau, D. A. Thompson, B. D. Hammock, and A. A. Spector Pathways of Epoxyeicosatrienoic Acid Metabolism in Endothelial Cells. IMPLICATIONS FOR THE VASCULAR EFFECTS OF SOLUBLE EPOXIDE HYDROLASE INHIBITION J. Biol. Chem., April 27, 2001; 276(18): 14867 - 14874. [Abstract] [Full Text] [PDF]
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D. C. Zeldin Epoxygenase Pathways of Arachidonic Acid Metabolism J. Biol. Chem., September 21, 2001; 276(39): 36059 - 36062. [Full Text] [PDF]
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B. B. Davis, D. A. Thompson, L. L. Howard, C. Morisseau, B. D. Hammock, and R. H. Weiss Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation PNAS, February 19, 2002; 99(4): 2222 - 2227. [Abstract] [Full Text] [PDF]
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