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J. Biol. Chem., Vol. 282, Issue 5, 2891-2898, February 2, 2007

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Compensatory Mechanism for Homeostatic Blood Pressure Regulation in Ephx2 Gene-disrupted Mice^*

Ayala Luria¹, Steven M. Weldon, Alisa K. Kabcenell, Richard H. Ingraham, Damian Matera, Huiping Jiang^¶, Rajan Gill^||, Christophe Morisseau^**, John W. Newman^||1, and Bruce D. Hammock^**2

From the Departments of Entomology and ^||Nutrition and the ^**Cancer Research Center, University of California, Davis, California 95616, the Departments of ^¶Translational Science and Cardiovascular Disease, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 06877, and the United State Department of Agriculture, ARS, Western Human Nutrition Research Center, Davis, California 95616

Arachidonic acid-derived epoxides, epoxyeicosatrienoic acids, are important regulators of vascular homeostasis and inflammation, and therefore manipulation of their levels is a potentially useful pharmacological strategy. Soluble epoxide hydrolase converts epoxyeicosatrienoic acids to their corresponding diols, dihydroxyeicosatrienoic acids, modifying or eliminating the function of these oxylipins. To better understand the phenotypic impact of Ephx2 disruption, two independently derived colonies of soluble epoxide hydrolase-null mice were compared. We examined this genotype evaluating protein expression, biofluid oxylipin profile, tissue oxylipin production capacity, and blood pressure. Ephx2 gene disruption eliminated soluble epoxide hydrolase protein expression and activity in liver, kidney, and heart from each colony. Plasma levels of epoxy fatty acids were increased, and fatty acid diols levels were decreased, while measured levels of lipoxygenase- and cyclooxygenase-dependent oxylipins were unchanged. Liver and kidney homogenates also show elevated epoxide fatty acids. However, in whole kidney homogenate a 4-fold increase in the formation of 20-hydroxyeicosatetraenoic acid was measured along with a 3-fold increase in lipoxygenase-derived hydroxylation and prostanoid production. Unlike previous reports, however, neither Ephx2-null colony showed alterations in basal blood pressure. Finally, the soluble epoxide hydrolase-null mice show a survival advantage following acute systemic inflammation. The data suggest that blood pressure homeostasis may be achieved by increasing production of the vasoconstrictor, 20-hydroxyeicosatetraenoic acid in the kidney of the Ephx2-null mice. This shift in renal metabolism is likely a metabolic compensation for the loss of the soluble epoxide hydrolase gene.

Received for publication, August 22, 2006 , and in revised form, November 28, 2006.

^* This work was supported in part by Grant R37 ES02710 from the NIEHS, National Institutes of Health, the NIEHS Superfund Basic Research Program P42 ES004699, NIEHS P30 ES05707, National Institutes of Health/NIEHS R01 ES013933, and the UCDMC Translational Technology Grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data, Tables S1–S3, and Fig. S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Entomology, University of California Davis, CA 95616. Tel.: 530-752-7519; Fax: 530-752-1537; E-mail: bdhammock{at}ucdavis.edu.

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