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Cytochromes P450 can metabolize endogenous fatty acids, such as arachidonic acid, to bioactive lipids such as epoxyeicosatrienoic acids (EETs) that have beneficial effects. EETs protect hearts against ischemic damage, heart failure or fibrosis; however, their effects are limited by hydrolysis to less active dihydroxy oxylipins by soluble epoxide hydrolase (sEH), encoded by the epoxide hydrolase 2 gene (EPHX2, EC 3.3.2.10). Pharmacological inhibition or genetic disruption of sEH/EPHX2 have been widely studied for their impact on cardiovascular diseases. Less well studied is the role of increased EPHX2 expression, which occurs in a substantial human population that carries the EPHX2 K55R polymorphism or after induction by inflammatory stimuli. Herein, we developed a mouse model with cardiomyocyte-selective expression of human EPHX2 (Myh6-EPHX2) that has significantly increased total EPHX2 expression and activity. Myh6-EPHX2 hearts exhibit strong, cardiomyocyte-selective expression of EPHX2. EPHX2 mRNA, protein, and epoxide hydrolysis measurements suggest that Myh6-EPHX2 hearts have 12-fold increase in epoxide hydrolase activity relative to wild type (WT) hearts. This increased activity significantly decreased epoxide:diol ratios in vivo. Isolated, perfused Myh6-EPHX2 hearts were not significantly different from WT hearts in basal parameters of cardiac function; however, compared to WT hearts, Myh6-EPHX2 hearts demonstrated reduced recovery of heart contractile function after ischemia and reperfusion (I/R). This impaired recovery after I/R correlated with reduced activation of PI3K/AKT and GSK3β signaling pathways in Myh6-EPHX2 hearts compared to WT hearts. In summary, the Myh6-EPHX2 mouse line represents a novel model of cardiomyocyte-selective overexpression of EPHX2 that has detrimental effects on cardiac function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background: Anorexia Nervosa (AN) is a serious mental illness characterized by emaciation, an intense fear of gaining weight despite being underweight, and distorted body image. Few treatments reverse the core symptoms in AN such as profound aversion to food and food avoidance. Consequently, AN has a chronic and relapsing course and the highest mortality rate of any psychiatric illness. A more complete understanding of the disease pathogenesis is needed in order to develop better treatments and improve AN outcome. The pathogenesis and psychopathophysiology of AN can be better elucidated by combining longitudinal phenotyping with multiple "omics" techniques, including genomics, proteomics, lipidomics, and metabolomics., Design: This paper summarizes the key findings of a series of interrelated studies including new experimental data and previously published data, and describes our current initiatives and future directions., Results: Exon sequencing data was analyzed in 1205 AN and 1948 controls. Targeted metabolomics, lipidomics, and proteomics data were collected in two independent convenience samples consisting of 75 subjects with eating disorders and 61 sex- and age-matched healthy controls. Study participants were female and the mean age was 22.9 (4.9 [SD]) years. Epoxide hydrolase 2 (EPHX2) genetic variations were significantly associated with AN risk, and epoxide hydrolase (sEH) activity was elevated in AN compared to controls. The polyunsaturated fatty acids (PUFAs) and eicosanoids data revealed that cytochrome P450 pathway was implicated in AN, and AN displayed a dysregulated postprandial metabolism of PUFAs and sEH-dependent eicosanoids., Implication and Current Initiatives: Collectively, our data suggest that dietary factors may contribute to the burden of EPHX2-associated AN susceptibility and affect disease outcome. We are implementing new investigations using a longitudinal study design in order to validate and develop an EPHX2 multi-omics biomarker system. We will test whether sEH-associated postprandial metabolism increases AN risk and affects treatment outcome through an ω-6 rich breakfast challenge. Participants will include 100 ill AN patients, 100 recovered AN patients, and 100 age- and race-matched healthy women. These data will allow us to investigate 1) how genetic and dietary factors independently and synergistically contribute to AN risk and progression, and 2) if clinical severity and treatment response in AN are affected by sEH activity and eicosanoid dysregulation. Results of our study will 1) identify clinically relevant biomarkers, 2) unravel mechanistic functions of sEH, and 3) delineate contributory roles of dietary PUFAs and cytochrome P450 pathway eicosanoids for the purpose of developing novel AN treatments and improving disease prognosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

P450 eicosanoids are important regulators of the cerebral microcirculation, but their role in cerebral small vessel disease is unclear. We tested the hypothesis that vascular cognitive impairment (VCI) is linked to reduced cerebral microvascular eicosanoid signaling. We analyzed human brain tissue from individuals formerly enrolled in the Oregon Brain Aging Study, who had a history of cognitive impairment histopathological evidence of microvascular disease. VCI subjects had significantly higher lesion burden both on premortem MRI and postmortem histopathology compared to age- and sex-matched controls. Mass spectrometry-based eicosanoid analysis revealed that 14,15-dihydroxyeicosatrienoic acid (DHET) was elevated in cortical brain tissue from VCI subjects. Immunoreactivity of soluble epoxide hydrolase (sEH), the enzyme responsible for 14,15-DHET formation, was localized to cerebral microvascular endothelium, and was enhanced in microvessels of affected tissue. Finally, we evaluated the genotype frequency of two functional single nucleotide polymorphisms of sEH gene EPHX2 in VCI and control groups. Our findings support a role for sEH and a potential benefit from sEH inhibitors in age-related VCI., (Copyright © 2014 Elsevier Inc. All rights reserved.)