POLYMORPHISM OF CYTOCHROME P450 EPOXYGENASE AND ITS ASSOCIATION WITH ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH CORONARY ARTERY DISEASE
Journal Title: INTERNATIONAL JOURNAL OF PURE MEDICAL RESEARCH - Year 2017, Vol 2, Issue 4
Abstract
Background: Cytochrome P450 (CYP) epoxygenase metabolise arachidonic acid (AA) into four epoxyeicosatrienoic acids (EETs) 5,6- EETs, 8,9 EETs, 11,12-EETs and 14,15-EETs. Since, EETs are unstable eicosanoids they rapidly get converted into dihydroxyeicosanoid trienoicacids (DHETs) by soluble hydrolase. These eicosanoids promote defence mechanism against inammatory atherosclerosis process. However, 11,12-EETs are more potent eicosanoids in maintaining anti-atherosclerotic activity. Endothelial dysfunction is the key step in the pathogenesis of atherosclerosis. Polymorphism in CYP epoxygenase can alter individual's risk for events in coronary artery disease (CAD) patients. Therefore, we examined the impact of CYP epoxygenase polymorphism indirectly through evaluation of 11,12-DHET levels and its association with endothelial dysfunction. Methods: It is a prospective case-control study consisting of 84 acute coronary syndrome (ACS) patients and 84 healthy controls of either gender aged above 18 years. Fasting serum lipid prole including total cholesterol ( TC), high density lipid (HDL), triglycerides (TG) and homocysteine levels were measured in all subjects. We measured plasma 11,12-dihydroxyeicosatrienoic acid (11,12-DHET) as indicative of 11,12-EETs. Genotyping of CYP putative exons of CYP2C9, CYP2C19 and CYP2J2 epoxygenase were carried out by Polymerase Chain Reaction–Single Strand Conformation Polymorphism (PCR-SSCP) method. Sanger's sequencing chain termination method was carried out for SSCP positive samples. All the data obtained were analysed by using Ms- Excel, 2007 and SPSS, version 24.Software, IBM, USA. Results: We observed signicantly higher levels of homocysteine in CAD group (35.1 ± 13.8 μmol/L) indicating higher inammatory condition in patients compared to control group (8.1 ± 2.9 μmol/L, p < 0.001). We also found higher 11,12-DHET levels in CAD group (628.6 ± 324.3 pg/mL) compared to healthy controls (332.1 pg/mL ± 203.2 pg/mL, p = 0.0001). In this connection, we observed positive correlation between homocysteine levels and 11,12- DHETs in CAD group (p = 0.01). Genotyping of CYP exons revealed 11 patients (13%) reporting 12 single nucleotide polymorphisms (SNPs). We found signicant difference in the levels of 11,12- DHETs between the patients reporting CYP polymorphism and patients without CYP polymorphism compared with the control (p<0.001). Further, we observed negative correlation between homocysteine levels and 11,12-DHETs in CAD patients reporting CYP polymorphisms indicating decline of DHET mediated anti-atherosclerotic activity Conclusions: Presence of lower levels of 11,12- DHETs is a reection of poor reserve defence mechanism in CAD patients that might cause endothelial dysfunction and risk of cardiac events. Therefore, genotyping of CYP2C9, CYP2C19 and CYP2J2 genes can be recommended to be used as prognostic marker for risk stratication in CAD patients.
Authors and Affiliations
Sowjenya Gopal, Rajasekhar Durgaprasad, Vanajakshamma Velam, Srinivasa Rao P. V. L. N, Sarma P. V. G. K
Keywords
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