Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene-disrupted mice.
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.
Luria
Ayala
A
Department of Entomology, University of California, Davis, CA 95616, USA.
Weldon
Steven M
SM
Kabcenell
Alisa K
AK
Ingraham
Richard H
RH
Matera
Damian
D
Jiang
Huiping
H
Gill
Rajan
R
Morisseau
Christophe
C
Newman
John W
JW
Hammock
Bruce D
BD
D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology*; D003433:Crosses, Genetic; D004851:Epoxide Hydrolases / Q000172:deficiency* / Q000235:genetics*; D004852:Epoxy Compounds / Q000378:metabolism; D005091:Exons; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D006801:Humans; D007668:Kidney / Q000502:physiology; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout
D004852:Epoxy Compounds; D005230:Fatty Acids, Nonesterified; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse