CYP2J2 Research Articles

A bioluminescent probe for imaging human cytochrome P450 2J2 activity in vitro and in vivo

Human Cytochrome P450 2J2 (CYP 2J2) is closely associated with various physiological diseases. However, bioluminescence (BL) tools for monitoring CYP 2J2 activity have not yet been reported. Herein, we rationally designed a BL probe, PJ-Luc, capable of real-time imaging of CYP 2J2. In vitro studies demonstrated that PJ-Luc can effectively respond to exogenous CYP 2J2 with high selectivity and a low detection limit (LOD = 0.11 nM). Further, living cell experiments indicated that PJ-Luc can accurately quantify the ratio of endogenous CYP 2J2 amounts in HepG-2-Luc and A549-Luc cells. Moreover, an ultrahigh BL signal-to-noise ratio (S/N = 2.3×105) was achieved in tumor-bearing mouse models. These results suggest that PJ-Luc has great potential in the diagnosis of tumors and other CYP-2J2-related diseases.

Pharmacogenetics and pharmacokinetics of rivaroxaban in patients with atrial fibrillation and chronic kidney disease

Aim. To study the possible relationship between polymorphic variants of ABCB1 (rs2032582, rs1045642, rs1128503), CYP3A5 (rs776746), CYP3A4 (rs35599367) and CYP2J2 (rs890293) genes with residual equilibrium concentrations (Cmin,ss) of rivaroxaban in patients with non-valvular atrial fibrillation (AF) and stage 3 and 4 chronic kidney disease (CKD).Material and methods. A total of 123 patients 52 to 97 years old (median age, 82 years) with AF in combination with stage 3 and 4 CKD were included in the study. Each patient underwent a pharmacogenetic and pharmacokinetic study.Results. Cmin,ss and dose-adjusted concentration (Cmin,ss/D) of rivaroxaban were significantly higher in patients with the TT genotype than with the CT genotype of the polymorphic variant rs1045642 of the ABCB1 gene (Сmin,ss 60,5 [36,7;173] ng/ml and 54,8 [23,1;97,3] ng/ml, respectively, р=0,016; Сmin,ss/D 4,06[2,3;8,1] ng/ml/mg and 2,2 [1,1;4,9] ng/ml/mg, р=0,006). In patients with the T allele (CT and TT genotypes), compared with CC genotype carriers, Cmin,ss and Cmin,ss/D were significantly higher (Cmin,ss 60,5 [36,7;173] ng/ml and 45,8 [20,9;82,3] ng/ml, respectively, p=0,029; Cmin,ss/D 4,06 [2,3;8,1] ng/ml/ mg and 2,6 [1,2;4,8] ng/ml/mg, respectively, p=0,014). Also, Cmin,ss and Cmin,ss/D was significantly higher in patients with the TT genotype according to the polymorphic variant rs2032582 of the ABCB1 gene than in patients with the GG genotype (p=0,02 and р=0,016 respectively). Cmin,ss and Cmin,ss/D in T allele (GT and TT genotypes) carriers were significantly higher than in T allele homozygotes (Cmin,ss 57,1 [27,7;106,0] ng/ml versus 37,6 [18,6;61,7] ng/ml respectively, p=0,024; Cmin,ss/D 3,6 [1,7;7,4] ng/ml/mg versus 2,3 [1,1;4,09] ng/ml/mg respectively, p=0,032). Differences in Сmin,ss and Сmin,ss/D of rivaroxaban were detected when comparing TC, CC and TT genotypes of polymorphism rs1128503 of the ABCB1 gene. When comparing Сmin,ss and Сmin,ss/D of rivaroxaban among carriers of AG and GG genotypes of the rs776746 polymorphism of the CYP3A56986A>G gene, no significance was detected (p>0,05). Also, no difference in Cmin,ss and Cmin,ss/D was found when comparing carriers of the CC and CT genotypes of the rs35599367 polymorphism of the CYP3A4 gene, and carriers of the CC and AC genotypes of the rs890293 polymorphism of the CYP2J2 gene (p>0,05).Conclusion. The carriage of T allele by polymorphic variants rs1045642 and rs2032582 of the ABCB1 gene affects Cmin,ss and Cmin,ss/D of rivaroxaban.

CYP2C8 and CYP2J2 gene variations increase the risk of hypertensive intracerebral hemorrhage

PurposeMany studies have shown that cytochrome P450 (CYP) gene polymorphisms are usually associated with an increased risk of cardiovascular and cerebrovascular diseases. To explore the association of CYP2C8 and CYP2J2 gene polymorphisms with hypertensive intracerebral hemorrhage (HICH) in the Han Chinese population. MethodsForty HICH patients and 40 control subjects were recruited for this study. Two single nucleotide polymorphisms (SNP) (rs1058932, rs2275622) in the CYP2C8 gene and two SNPs (rs2271800, rs1155002) in the CYP2J2 gene were selected for genotyping by direct sequencing. Statistical analysis was applied to examine the effect of genetic variation on HICH. ResultsWe found that variant alleles of CYP2C8 rs1058932 (A) and rs2275622 (C) were both significantly associated with HICH, especially in females. We also found significant associations of CYP2C8 rs1058932 (A) and rs2275622 (C) variant alleles with poor outcomes in HICH patients, especially in males. ConclusionsCYP2C8 gene polymorphisms might increase the risk of HICH in the Han Chinese population and might lead to poor outcomes. This finding adds to the body of literature supporting novel therapeutic strategies for HICH.

Variants in CYP2J2 and CYP2C9 Contribute to Susceptibility of Lung Cancer.

Cytochrome P450 (CYP) enzymes are involved in the metabolism of xenobiotic and carcinogen. In the study, we evaluated the association of CYP2J2 and CYP2C9 variants with lung cancer. Five polymorphisms in CYP2J2 and four polymorphisms in CYP2C9 were genotyped in 507 lung cancer patients and 505 controls with Agena MassARRAY platform. The linkage of variants with lung cancer risk was evaluated by odds ratio (OR) and 95% confidence interval (CI) in genetic models and haplotype analyses. We found that CYP2C9 rs1934967 alleles were associated with lung cancer risk (P < 0.05). In stratified analysis, rs2280274 (women, non-smoker, non-drinker and lymphatic metastasis), rs11207535 (non-smoker and non-drinker), rs10889159 (non-smoker and non-drinker) of CYP2J2, whereas rs1934967 (age ≤ 60m, BMI > 24, squamous carcinoma) of CYP2C9 decreased lung cancer risk (P < 0.05). In addition, the results of linkage disequilibrium (LD) analysis showed that rs2280274|rs4388726 - TG (with adjustment: P = 0.042) of CYP2J2 and rs10509679|rs1934967|rs1934968|rs9332220 - GTGG (without adjustment: P = 0.044) of CYP2C9 were linked with a significantly decreased lung cancer risk. Our results indicated genetic variants in CYP2J2 and CYP2C9 might contribute to the susceptibility of lung cancer in Chinese population.

Neovasculogenic effect of 11,12-epoxyeicosatrienoic acid involves the Akt/eNOS signaling pathways in human endothelial progenitor cells.

The 11,12-epoxy-eicosatrienoic acid (11,12-EET) is formed from arachidonic acid (AA) by cytochrome P450 2J2 (CYP 2J2) epoxygenase and function as an effector in blood vessels. Human endothelial progenitor cells (hEPCs), a preceding cell source for endothelial cells (ECs), involve in the vascular tissue repairing by postnatal neovasculogenesis. However, the effect of 11, 12-EET on hEPCs and neovasculogenesis is not well known. In the current study, we examined the function of 11, 12-EET in hEPCs-mediated neovasculogenesis by using tubular formation analysis, Western Blotting assay, immunofluorescence staining, flow cytometry analysis and zymogram analysis. The results suggest that 11, 12-EET significantly induces neovasculogenesis through the phosphorylation of phosphoinositide 3-kinase (PI3-K)/Akt, endothelial-nitric oxide synthase (e-NOS) and extracellular signal-regulated kinase 1/2 (ERK 1/2) signaling pathways. 11, 12-EET up-regulates the expression of cyclin D1, cyclin-dependent kinase 4 (CDK4) and nuclear factor kappa B (NF-κB) proteins. Moreover, 11, 12-EET augments the expression of VE-cadherin and CD31 proteins in hEPCs. 11, 12-EET also augmented Rac1/Rho A signaling cascades, cell migration and an up-regulation of matrix metalloproteinase (MMP) -2 and -9 proteins. These results demonstrate that 11, 12-EET exerts a significant function in the neovasculogenesis of hEPCs.

CYP2J2 Is a Diagnostic and Prognostic Biomarker Associated with Immune Infiltration in Kidney Renal Clear Cell Carcinoma.

Cytochrome P450 family 2 subfamily J member 2 (CYP2J2), a member of the monooxygenase cytochrome P450 (CYP) family and the only member of the human CYP2J subfamily, has many functions, including regulation of oxidative stress, inflammation, apoptosis, and immune responses. However, its role in cancer development has not been clearly elucidated. In this study, expression levels of CYP2J2 in various cancer types were determined using the Oncomine, the Gene Expression Profiling Interactive Analysis (GEIPA), DriverDBv3, UALCAN, and Tumor Immune Estimation Resource (TIMER) databases. The prognostic value of CYP2J2 for KIRC was analyzed using GEPIA, UALCAN, OSkirc, and DriverDBv3 databases. We evaluated the expression levels of CYP2J2 transcript, protein, and promoter methylation at different clinical characteristics in KIRC through the UALCAN database. Simultaneously, CYP2J2 network-related functions were evaluated using the GeneMANIA interactive tool while the biological processes involved in CYP2J2 and its interactive genes were investigated through Metascape and FunRich. Then, we used TIMER to determine the correlation between CYP2J2 expression levels and immune infiltration levels in KIRC. In KIRC, the CYP2J2 gene, RNA, and protein were found to be overexpressed. However, the methylation level of CYP2J2 promoter in KIRC was lower than in normal tissues. Surprisingly, elevated expression levels of CYP2J2 exhibited better prognostic outcomes in KIRC. Evaluation of protein-protein interaction networks and biological processes revealed that CYP2J2 was principally involved in immune responses, apoptosis, and other metabolic processes. Moreover, we found that the expression levels of CYP2J2 were positively correlated with infiltration levels of B cells, CD8 + T cells, neutrophils, and dendritic cells in KIRC. Therefore, we speculated that the overexpression of CYP2J2 prolonged the survival outcome of KIRC patients, which may be related to the change of tumor immune microenvironment. Moreover, all these new understandings of CYP2J2 may provide important value for the early diagnosis and new targeted drug therapy of KIRC.

Association of CYP2J2 Gene Polymorphism with Ischemic Stroke

Abstract Background Stroke is regarded as a severe disorder with high morbidity and high mortality, which is a major healthcare problem and a serious economic burden worldwide. It claims over 6 million deaths each year worldwide. Aim To investigate the association of CYP2J2 gene polymorphism with increased risk of ischemic stroke in a group of Egyptian patients. Subjects and Methods This study was conducted at Clinical Pathology and Stroke Units of Ain Shams University Hospitals, between November 2017 and July 2018. A total number of 30 subjects were included (20 patients and 10 controls). Results Our study concluded that risk of hypertension is higher in heterozygous GT population (100%) compared to the wild type (51.22%), whereas no significant increase in the ischemic stroke risk was observed between wild and heterozygous groups. Conclusion The most frequent genotype among the chosen sample of Egyptian population in the study (acute ischemic stroke patients and controls) was the wild TT genotype although not statistically different than other genotypes.

Cytochrome 2J2 (CYP2J2) Gene Polymorphism in Coronary Artery Disease

AbstractBackground: Coronary artery disease is a multifactorial disease where genetic risk factors are targeted by the environ-mental risk factors leads to disease pathogenesis. CYP2J2 is a monooxygenase which metabolize arachidonic acid into cardioprotective compounds. Genetic polymorphisms in CYP2J2 are common especially CYP2J2*7 (rs890293) which reduce CYP2J2 gene expression and subsequently its cardio-protective effects.Aim of Study: The aim of the present case control study to investigate the relation between CYP2J2*7 (G-50T) (rs890293) gene polymorphism and coronary artery disease (CAD) susceptibility and severity in a cohort of Egyptian individuals.Patients and Methods: The study was conducted on 50 CAD patients and 50 age and sex-matched apparently healthy individuals. Assay of CYP2J2*7 gene SNP (rs890293) was performed by PCR amplification and Restriction Fragment Length Polymorphism (PCR-RFLP) technique.Results: Our results revealed that the genotypic and allelic frequencies of G-50T didn't show any statistically significant association neither with the susceptibility of coronary artery disease or with the number of significantly diseased coronaries. Also no statistically significant difference between GG gen-otypes patients and GT genotypes patients as regard risk factors for CAD.Conclusions: There was no significant association between CYP2J2*7 gene polymorphism (G-50T) (rs890293) and risk of coronary artery disease and also no association between this gene polymorphism and the severity of CAD in the sample of Egyptian population included in this study.

Reversal Effect of Pioglitazone on Multidrug Resistance in K562/ADR Cells and Its Mechanism

To explore the reversal effect of pioglitazone (PIO) on multidrug resistance in K562/ADR cells and its mechanism. The proliferation inhibition rate, half inhibition concentration (IC50) and drug-resistance reversal multipe were detected and the curve of proliferation inhibition rate was drawn by MTT assay, the transcription of PPARγ, CYP2C8 and CYP2J2 genes was detected by RT-PCR; the expression of PPARγ, CYP2C8 and CYP2J2 proteins was detected by Western blot. The IC50 of PIO on K562 and K562/ADR cells for 60 h was 326.7 μmol/L and 349.1 μmol/L respectively. The reversal multiple of 30 μmol/L PIO on ADR-resistance of K562/ADR cells was 6.4. After treatment of K562/ADR cells with PIO, the transcription of CYP2C8 and CYP2J2 and the protein expression of CYP2C8 and CYP2J2 significantly decreased, the transcription of PPARγ gene and the expression of PPARγ protein were not changed. Pioglitazone can reverse the adriamycin-resistance in K562/ADR cells that is closely related to the decrease of protein expression of CYP2C8 and CYP2J2. Pioglitazone is an effective multidrug resistance reversal agent for tumors.

Associations between CYP2J2 (-76G>T) rs890293 polymorphism and age-related macular degeneration.

To determine the relation between early stage and exudative AMD and CYP2J2 (-76G>T) gene rs890293 polymorphism in a Lithuanian population. The study enrolled 204 patients with early AMD, 197 patients with exudative AMD and 198 healthy controls. Samples of DNA from peripheral white blood cells were purified using commercial kits. The genotyping was carried out using a real-time PCR method. The CYP2J2 (-76G>T) rs890293 TT genotype in patients with early AMD was statistically significantly less frequent than in the control group: 0% vs. 2.5% (P=0.028). There were no significant differences in rs890293 gene polymorphisms between the exudative AMD and control groups. Also, the CYP2J2 (-76G>T) rs890293 TT genotype was statistically significantly less frequent in older early AMD patients (≥65 years) compared to control group persons (≥65 years): 0% vs. 5.4% (P=0.03). The CYP2J2 (-76G>T) TT genotype may be associated with reduced manifestation of early stage AMD; therefore, a larger sample size is required for further analysis.

Differential Expression of Prostaglandin I2 Synthase Associated with Arachidonic Acid Pathway in the Oral Squamous Cell Carcinoma.

Introduction Differential expression of genes encoding cytochrome P450 (CYP) and other oxygenases enzymes involved in biotransformation mechanisms of endogenous and exogenous compounds can lead to oral tumor development. Objective We aimed to identify the expression profile of these genes, searching for susceptibility biomarkers in oral squamous cell carcinoma. Patients and Methods Sixteen oral squamous cell carcinoma samples were included in this study (eight tumor and eight adjacent non-tumor tissues). Gene expression quantification was performed using TaqMan Array Human CYP450 and other Oxygenases 96-well plate (Applied Biosystems) by real time qPCR. Protein quantification was performed by ELISA and IHC methods. Bioinformatics tools were used to find metabolic pathways related to the enzymes encoded by differentially expressed genes. Results. CYP27B1, CYP27A1, CYP2E1, CYP2R1, CYP2J2, CYP2U1, CYP4F12, CYP4X1, CYP4B1, PTGIS, ALOX12, and MAOB genes presented differential expression in the oral tumors. After correction by multiple tests, only the PTGIS (Prostaglandin I2 Synthase) gene presented significant differential expression (P < 0.05). The PTGIS gene and protein were reduced in oral tumors. Conclusion PTGIS presents downexpression in oral tumors. PTGIS play an important role in the arachidonic acid metabolism. Arachidonic acid and/or metabolites are derived from this pathway, which can influence the regulation of important physiological mechanisms in tumorigenesis process.

Molecular cloning and characterization of the novel CYP2J2 in dromedary camels (Camelus dromedarius)

Although its economic, cultural and biological importance, many genes haven't been depicted, sequenced or analyzed to date for Camelus dromedarius. In the present paper, the full-length c-DNA of a novel CYP2J2 (GenBank accession number MH511989) was cloned from liver, heart, and kidney mRNA by RACE-PCR. The full-length c-DNA of the cloned CYP2J2 was sequenced and analyzed using bioinformatics methods. The full-length c-DNA sequence was 2135 bp with no introns. The open reading frame (ORF) had 1341 nucleotides which coded for a putative protein of 446 amino acids. The deduced protein is located in the endoplasmic reticulum. It has two transmembrane regions. The nucleotides and deduced amino acids sequences of the cloned CYP2J2 were 1400 nucleotides and 47 amino acids shorter than the predicted homolog respectively. This study is the first description of the putative CYP2J2 gene, which opens the way to a new investigation-so far-never accomplished in Camelus dromedarius.

Genetic polymorphisms of the drug-metabolizing enzyme CYP2J2 in a Tibetan population.

As an important metabolic enzyme, it is necessary to investigate the genetic polymorphisms of CYP2J2 among healthy Tibetan individuals. Genetic polymorphisms of CYP2J2 could affect enzyme activity and lead to differences among individual responses to drugs.We sequenced the whole gene of CYP2J2 in 100 unrelated, healthy Tibetan volunteers from the Tibet Autonomous Region and screened for genetic variants in the promoters, introns, exons, and the 3′-UTR regions.We detected 4 novel genetic polymorphisms of the CYP2J2 gene. The allelic frequencies of CYP2D6∗1 and ∗7 were 0.955 and 0.045, respectively. CYP2D6∗1/∗7 decreased the activity of CYP2J2 and was expressed in 9% of the sample population.Our results provided basic data about CYP2J2 polymorphisms in a Tibetan population, suggested that the enzymatic activities of CYP2J2 might be different within the ethnic group, and offered a theoretical basis for individualized medical treatment and drug genomics studies.

Genetic polymorphisms of CYP2S1, CYP2J2 and CYP2R1 genes in three Chinese populations: Han, Tibetan and Uighur

Cytochrome P450 enzymes CYP2S1, CYP2J2and CYP2R1 are of interest due to their unknown enzymatic function and disease-specific expression property. The aim of this study was to investigate the genetic variations of CYP2S1, CYP2J2 and CYP2R1 genes, and their polymorphic distribution in different Chinese populations. All of the exons, exon-intron boundaries and 1kb 5'-flanking region of the three genes were sequenced in 150 Chinese subjects. There were21, 15 and nine genetic variants identified in CYP2S1, CYP2J2and CYP2R1 genes, respectively. The genetic polymorphisms of CYP2S1 and CYP2J2 showed significant difference. Thr353Ala variant in CYP2S1 protein was predicted to be consistently damaged. The hydrogen bond interactions were decreased in two mutants: Thr353Ala and Cys372Ser. -177C >T in CYP2S1 affected transcription factor EGR1 binding site. This study highlights the importance of genetic polymorphism information on the CYP2S1, CYP2J2 and CYP2R1 genes in Chinese populations.

Time-dependent expression pattern of cytochrome P450 epoxygenases and soluble epoxide hydrolase in normal human placenta

CYP2C and CYP2 J enzymes, commonly named as cytochrome P450 (CYP) epoxygenases, convert arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EETs), biologically active eicosanoids with many functions in organism. EETs are rapidly hydrolysed to less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). We investigated spatio-temporal expression pattern of CYP2C8, CYP2C9, CYP2 J2 and sEH in normal human placenta by immunohistochemical method. In the villous trophoblast, CYP2C8 was the most abundant protein. Its expression is higher than the CYP2C9 and CYP2 J2 in the cytotrophoblast in the embryonic stage of development and remains higher in syncytiotrophoblast of term placenta. Unlike to CYP2C8, CYP2C9 and CYP2 J2 expression decrease in term placenta. sEH expression increases with gestation age and is strictly limited to cytotrophoblast in embryonic and foetal stages of the development. Moreover, CYP2C8 shows more intensive staining than the other protein monitored in Hofbauer cells in villous stroma. Specific information regarding the exact role of EETs and DHETs functions in a normal placenta is still unknown. Based on CYP epoxygenases and sEH localization and well known information about the functions of placental structures during development, we suggest that these enzymes could play different roles in various cell populations in the placenta. As the placenta is absolutely crucial for prenatal development, arachidonic acid is essential part of human nutrient and CYP epoxygenases expression can be affected by xenobiotics, further investigation of the exact role of CYP epoxygenases, sEH, and their metabolites in normal pregnancy and under pathological conditions is needed.

CYP2J2-derived EETs attenuated ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis

Chronic excessive drinking leads to myocardial contractile dysfunction and dilated cardiomyopathy, where ethanol toxicity plays an essential role. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the cardiovascular system, but their role in alcoholic cardiomyopathy is elusive. This study was designed to evaluate the effects and mechanisms of CYP2J2 gene delivery on ethanol-induced myocardial dysfunction with focus on autophagy and apoptosis. C57BL/6 J mice were challenged with a 4% Lieber-DeCarli ethanol liquid diet for 8 weeks, before which rAAV9-CYP2J2 was injected via the tail vein. Cardiac function was assessed using echocardiography, hemodynamic measurement, and cardiac histology. The results showed that chronic ethanol intake led to cardiac dilation, contractile dysfunction, cardiomyocyte hypertrophy, oxidative stress, and cardiomyocyte apoptosis, while CYP2J2 overexpression ameliorated these effects. Additionally, chronic ethanol consumption triggered myocardial autophagosome formation, but impaired autophagic flux via disrupting autophagosome-lysosome fusion, as evidenced by increased LC3 II/I, Beclin-1 and SQSTM1 levels, but reduced LAMP-2 expression. Interestingly, rAAV9-CYP2J2 treatment exerted cardioprotection via restoring autophagic flux in the alcoholic myocardium. Similarly, exogenous 11,12-EET addition significantly restored ethanol-induced neonatal rat cardiomyocyte autophagic flux impairment and inhibited apoptosis, both of which were mediated by AMPK/mTOR signaling pathway in vitro. In conclusion, our data suggest that CYP2J2-derived EETs attenuate ethanol-induced myocardial dysfunction through inducing autophagy and reducing apoptosis.

Screening and identification of candidate genes essential for cervical lymph node metastasis in nasopharyngeal carcinoma with microarrays

The aim of the present study is to identify genes that are crucial for the cervical lymph node metastasis, which predicts poor prognosis of nasopharyngeal carcinoma (NPC), endemic in southern China. Microarrays with probes to determine genomic expression profile and promoter methylation status in tumor specimens were used, to test cDNA reversely transcribed from total RNA isolated from the samples. More than 3, 000 genes with downregulated and upregulated differential expression, and 33 genes with differential methylation were identified. Among them, expression of BAZ2B, CYP2J2 and ZNF628 were reduced due to promoter hypermethylation. Gene Ontology and pathway analysis were performed using online databases including Bioconductor and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. In summary, genes as biomarkers for prognosis of NPC were screened, and BAZ2B, CYP2J2 and ZNF628 were related to lymph node metastasis

Association of CYP2J2 gene polymorphisms with ischemic stroke and stroke subtypes in Chinese population

Background and purpose:Ischemic stroke (IS) is the main cause of mortality and disability among the old people in China and is a multifactorial disease influenced by many factors including genetic factors like the allele for CYP 2J2. It has been demonstrated that CYP2J2 polymorphisms alter the transcriptional activity. However, studies on the association between CYP2J2-50G/T polymorphism and IS have reported conflicting results. Thus, our study aimed to examine the association between 4 variants in the CYP2J2 gene and the risk of IS and its subtypes, in the Chinese population.Materials and Methods:In this study, genotyping was performed by using polymerase chain reaction (PCR) sequencing for 202 IS patients and 206 age- and sex-matched controls. Odds ratios (ORs) and confidence interval (CI) were estimated by multivariate logistic regression and PCR results were confirmed by DNA sequencing. A meta-analysis was conducted to evaluate the association of CYP2J2–50G>T polymorphism with the risk of IS in Chinese population by calculating pooled OR.Results:We found this polymorphism was significantly associated with IS (17.82% vs. 10.68%, P = 0.039). Multiple logistic regression analysis revealed that GT genotype was associated with a significantly high risk of IS (OR = 2.32, 95% CI: 1.21–4.45, P = 0. 011) after adjustment for other confounding factors such as hypertension, diabetes, heart disease, smoking habit, family history, triglyceride and low-density lipoprotein levels. We also found a significant association of GT genotype with small artery occlusion (SAA) (P < 0.05; OR = 2.22; 95% CI: 1.043–4.72). Meta-analysis results also showed that the GT genotype carriers had a negative effect on the risk of IS in Chinese population with overall OR of 1.40 (95% CI: 1.06–1.84).Conclusion:The findings of the present study suggested that polymorphism in −50G/T position of CYP2J2 gene might be a risk factor for IS in Chinese population. Further large prospective studies were required to confirm these findings.

Gene- gene interaction between CYP2J2 and PPAR -γ gene on late-onset Alzheimer’s disease in the eastern Chinese Han population

AimsTo investigate the impact of PPAR -γ and CYP2J2 gene single nucleotide polymorphisms (SNPs) and gene- gene interactions on late-onset Alzheimer’s disease (LOAD) risk in Chinese Han population. MethodsA total of 880 participants (514 males, 366 females), with a mean age of 81.7±15.9years old are selected, including 430 LOAD patients and 450 normal participants. Generalized multifactor dimensionality reduction (GMDR) is used to examine interaction among six SNPs, odds ratio (OR) and 95% confident interval (95%CI) are calculated by Logistic regression model. ResultsLogistic regression analysis showed that increased LOAD risks are associated with T allele of the rs1155002 polymorphism, adjusted OR (95%CI)=1.46 (1.12–1.90), and T allele of the rs890293 polymorphism, adjusted OR (95%CI)=1.65 (1.30–2.06), and G allele of the rs1805192 polymorphism, adjusted OR (95%CI)=1.70 (1.25–2.27). We also found a potential gene–gene interaction between rs890293 and rs1805192. Participants with GT or TT of rs890293 and CG or GG of rs1805192 genotype have the highest LOAD risk, compared to participants with GG of rs890293 and CC of rs1805192 genotype, OR (95%CI)=2.22 (1.63 –2.85), after covariates adjustment. Conclusionsrs1155002, rs890293 and rs1805192 polymorphism are associated with increased LOAD risk. Participants with GT or TT of rs890293 and CG or GG of rs1805192 genotype have the highest LOAD risk.

CYP2J2-Derived EETs Attenuated Angiotensin II-Induced Adventitial Remodeling via Reduced Inflammatory Response

Background: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids (AA) to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the treatment of cardiovascular diseases, but little is known about its role on adventitial remodeling. Methods: We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts (AFs) in vitro treated with Angiotensin II to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling. Results: CYP/sEH system was found to exist in human adventitia, and involved in adventitial remodeling process. Exogenous EETs administration significantly inhibited Ang II-induced AFs activation, characterized by differentiation, proliferation, migration, and collagen synthesis. These protective effects were partially reversed by PPARγ antagonist GW9662 pretreatment or SOCS3 siRNA transfection. EETs suppressed Ang II-induced IκBα phosphorylation, subsequent NF-κB nuclear translocation via PPARγ dependent signaling pathway in AFs. Additionally, EETs reduced Ang II-induced JAK2, STAT3 phosphorylation and subsequent phosphor-STAT3 nuclear translocation, which were mediated by SOCS3 induction but independent of PPARγ activation. Furthermore, rAAV-CYP2J2 gene delivery reduced vessel wall thickening, AFs differentiation, proliferation and collagen deposition in aortic adventitia induced by Ang II infusion, which were mediated by NF-κB and SOCS3/JAK/STAT signaling pathways in blood pressure dependent and independent manner, respectively. Conclusion: We concluded that CYP2J2 overexpression attenuated Ang II-induced adventitial remodeling via PPARγ-dependent NF-κB and PPARγ-independent SOCS3/JAK/STAT inflammatory signaling pathways.