Dataset Information

Transcriptional regulation of the human soluble epoxide hydrolase gene EPHX2.

ABSTRACT: Soluble epoxide hydrolase (sEH) is a multifunctional protein encoded by the EPHX2 gene. The biological functions and enzyme kinetics of sEH have been extensively investigated, however, little is known about its transcriptional regulation and mechanisms of tissue specific expression. Here, a luciferase gene based reporter assay was used to identify the minimal promoter and cis regulatory elements of EPHX2. The minimal promoter was identified as a GC-rich region between nts -374 and +28 with respect to the putative transcriptional start site. A reporter plasmid carrying this minimal promoter showed higher or similar activities in comparison to a reporter plasmid carrying nts -5,974 to +28 of EPHX2 in 9 human cell lines that were tested. Sp1 binding sites that are involved in augmenting the minimal promoter activity of EPHX2 were identified by nested deletion analysis, site-specific mutation, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay.

SUBMITTER: Tanaka H

PROVIDER: S-EPMC2699939 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Transcriptional regulation of the human soluble epoxide hydrolase gene EPHX2.

Tanaka Hiromasa H Kamita Shizuo G SG Wolf Nicola M NM Harris Todd R TR Wu Zhaoju Z Morisseau Christophe C Hammock Bruce D BD

Biochimica et biophysica acta 20071203 1

Soluble epoxide hydrolase (sEH) is a multifunctional protein encoded by the EPHX2 gene. The biological functions and enzyme kinetics of sEH have been extensively investigated, however, little is known about its transcriptional regulation and mechanisms of tissue specific expression. Here, a luciferase gene based reporter assay was used to identify the minimal promoter and cis regulatory elements of EPHX2. The minimal promoter was identified as a GC-rich region between nts -374 and +28 with respe ...[more]

PMID: 18078836

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Project description:Soluble epoxide hydrolase 2 (EPHX2) is an enzyme promoting increased cellular apoptosis through induction of oxidative stress (OS) and inflammation. The EPHX2 gene which encodes soluble EPHX2 might be implicated in the pathogenesis and development of OS and atherosclerosis. We aimed to assess the possible association between two functional polymorphisms of the EPHX2 gene (rs2741335 and rs11780592) with oxidized LDL (ox-LDL), carotid atherosclerosis, mortality, and cardiovascular (CV) disease in 118 patients with diabetic chronic kidney disease (CKD). At baseline, ox-LDL and carotid intima-media thickness (cIMT) were evaluated and all patients were followed for seven years with outcomes all-cause mortality and CV events. rs11780592 EPHX2 polymorphism was associated with ox-LDL, cIMT, albuminuria, and hypertension. Compared to AG and GG, AA homozygotes had higher values of albuminuria, ox-LDL, and cIMT (p = 0.046, p = 0.003, and p = 0.038, respectively). These associations remained significant, even after grouping for the G allele. After the follow-up period, 42/118 patients died (30/60 with AA genotype, 11/42 with AG genotype, and 1/12 with GG genotype) and 49/118 experienced a new CV event (fatal or nonfatal). The Kaplan-Meier analysis revealed that patients with the AA genotype exhibited a significantly higher mortality risk, compared to patients with AG and GG genotypes (p = 0.006). This association became even stronger, when AG and GG genotypes were grouped (AA vs. AG/GG, p = 0.002). AA homozygotes were strongly associated with all-cause mortality in both univariate (hazard ratio (HR) = 2.74, confidence interval (CI) = 1.40-5.35, p = 0.003) and multivariate Cox regression analysis (HR = 2.61, CI = 1.32-5.17, p = 0.006). In conclusion, our study demonstrated that genetic variations of EPHX2 gene were associated with increased circulating ox-LDL, increased cIMT, and all-cause mortality in diabetic CKD. Since EPHX2 regulates the cholesterol efflux and the oxidation of LDL in foam cells and macrophages, our study suggests that a genetic basis to endothelial dysfunction and OS might be present in diabetic CKD.

Dataset Information

Transcriptional regulation of the human soluble epoxide hydrolase gene EPHX2.

Publications

Transcriptional regulation of the human soluble epoxide hydrolase gene EPHX2.

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