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

作者：AYALA R LURIA, Steven M. Weldon, Alisa K. Kabcenell, Richard H. Ingraham, Damian Matera, Huiping Jiang, Rajan Gill, Christophe H.P. Morisseau, John W. I. Newman, Bruce D. Hammock · 发表于：Journal of Biological Chemistry · 年份：2006 · DOI：10.1074/jbc.m608057200 · 被引用次数：145 · 研究领域：Eicosanoids and Hypertension Pharmacology、Hormonal Regulation and Hypertension、Alcohol Consumption and Health Effects

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 s...