|Luria, Ayala - UCD, ENTOMOLOGY DEPT.|
|Weldon, Steven - BOEHRINGER INGELHEIM PHAR|
|Kabcenell, Alisa - BOEHRINGER INGELHEIM PHAR|
|Ingraham, Richard - BOEHRINGER INGELHEIM PHAR|
|Matera, Damian - BOEHRINGER INGELHEIM PHAR|
|Jiang, Huiping - BOEHRINGER INGELHEIM PHAR|
|Gill, Rajan - UCD, ENTOMOLOGY & NUTR.|
|Morisseau, Christophe - UCD, ENTOMOLOGY|
|Hammock, Bruce - UCD, ENTOMOLOGY PROF.|
Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 28, 2006
Publication Date: February 2, 2007
Citation: Luria, A., Weldon, S.M., Kabcenell, A.K., Ingraham, R.H., Matera, D., Jiang, H., Gill, R., Morisseau, C., Newman, J.W., Hammock, B.D. Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene disrupted mice. 2007. Journal of Biological Chemistry. Vol.282,No.5:12891-2898. Interpretive Summary: Arachidonic acid is an essential omega-6 polyunsaturated fatty acid that is transformed into a variety of metabolites which play roles in the regulation of blood pressure and inflammation. The epoxides of arachidonic acid are one such group of metabolites which can reduce blood pressure and inflammation. These compounds are degraded by the soluble epoxide hydrolase. When the soluble epoxide hydrolase gene, Ephx2, was deleted in mice, blood pressure was initially reduced in males, but not females. However, with continued breeding, this effect on blood pressure was lost. In this study, we investigated the mechanism of this loss in a low blood pressure phenotype to better understand the linkage between complex metabolic networks that interact to control blood pressure. What we observed was that the soluble epoxide hydrolase null mice showed increased plasma epoxy fatty acids, decreases in their soluble epoxide hydrolase-dependent metabolites, while measured levels of lipoxygenase- and cyclooxygenase-dependent oxylipins were unchanged. Similar changes were seen in liver metabolism. However, in whole kidney homogenate a four-fold increase in the formation of 20-hydroxyeicosatetrenoic acid was measured along with a three-fold increase in lipoxygenase derived hydroxylation and prostanoid production. These metabolites can oppose the blood pressure reductions in the soluble epoxide hydrolase null mouse by constricting blood vessels and reducing sodium, and thus water, excretion. This shift in renal metabolism is likely a metabolic compensation for the loss of the soluble epoxide hydrolase gene. Therefore, if the therapeutic use of soluble epoxide hydrolase inhibitors reaches the clinic, combinations with arachidonic acid omega-hydroxylase inhibitors and or diuretics may be help them retain their efficacy.
Technical Abstract: 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 further examined this genotype evaluating protein expression, biofluid oxylipin profile, tissue oxylipin production capacity and blood pressure. Ephx2gene 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 four-fold increase in the formation of 20-hydroxyeicosatetrenoic acid was measured along with a three-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-hydroxyeicosatetrenoic acid in kidney of the Ephx2-null mice. This shift in renal metabolism is likely a metabolic compensation for the loss of soluble epoxide hydrolase gene.