Characterization of transgenic mice with neuron-specific expression of soluble epoxide hydrolase

Abstract

Soluble epoxide hydrolase (sEH) is the major enzyme responsible for the metabolism and inactivation of epoxyeicosatrienoic acids (EETs). EETs are produced by the cytochrome P450 (CYP) epoxygenase pathway of arachidonic acid (AA) metabolism and tend to be anti-hypertensive, anti-inflammatory and protective against ischemic injury. Since the metabolism of EETs by sEH reduces or eliminates their bioactivity, inhibition of sEH has become a therapeutic strategy for hypertension and inflammation. sEH is found in nearly all tissues so the systemic application of inhibitors is likely to affect more than blood pressure and inflammation. In the central nervous system, EETs are thought to play a role in the regulation of local blood flow, protection from ischemic injury, inhibition of inflammation, the release of peptide hormones and modulation of fever. However, little is known about region- and cell-specific expression of sEH in the brain. In the mouse brain, expression of sEH was found widely in cortical and hippocampal astrocytes and also in a few specific neuron-types in the cortex, cerebellum, and medulla. To assess the functional significance of neuronal sEH, we generated a transgenic mouse model, which over-expresses sEH specifically in neurons. Transgenic mice showed increased neuron labeling in cortex and hippocampus with little change in labeling of other brain regions. Despite a 3-fold increase in sEH activity in the brain, there was no change in arterial pressure. This data provides new information required for studying the central roles of the cytochrome P450 epoxygenase pathway.

Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

“…However, it was found that the mechanism of protection by AUDA-BE was not due to vascular effects that would be characteristic of arachidonic acid-derived EETs or altered ischemic severity, as determined by blood flow rates. This suggests an alternate mechanism for the protection by AUDA-BE and is in agreement with the findings of another recent study demonstrating that in transgenic mice with neuronspecific overexpression of soluble epoxide hydrolase there was no change in arterial blood pressure (Bianco et al, 2009). Given that AUDA inhibits epoxide hydrolasemediated metabolism of 5,6-EET-EA (Snider et al, 2009), it is possible that the observed protective mechanism of AUDA-BE in ischemic stroke may in part be due to prolongation of the action of endogenous 5,6-EET-EA at the CB2 receptor on microglia and/or infiltrating lymphocytes.…”

Epoxyeicosatrienoic Acids, Hypertension, and Kidney Injury

“…75 In contrast, neuronal specific expression of sEH to increase activity 3-fold failed to increase arterial blood pressure in mice. 76 Sex differences have also been found with regards to blood pressure regulation. Basal blood pressure in Ephx2 -/- mice was lower in males but not females when compared to wild-type mice.…”

Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism

“…The enzyme is widely distributed in human tissues, with the largest amounts in liver, kidney, intestine, and the vasculature. sEH also is present in brain, and while it is expressed in some neurons, it is contained mostly in cortical and hippocampal astrocytes [40–42]. sEH functions as a 120 kDa homodimer, and dimerization is required for enzymatic activity [43].…”