title: Oxidative stress in coronary artery disease: epigenetic perspective.
abstract: The association between oxidative stress and coronary artery disease (CAD) is well documented. However, the role of epigenetic factors contributing to oxidative stress is relatively unexplored. In this study, we aimed to explore the impact of DNA methylation profile in BCL2/E1B adenovirus interacting protein 3 (BNIP3), extracellular superoxide dismutase (EC-SOD) and glutathione-S-transferase P1 (GSTP1) on the oxidative stress in CAD. Further, the contribution of folate pathway genetic polymorphisms in regulating epigenome was elucidated. The expression of BNIP3, EC-SOD, and GSTP1 were studied by using Maxima@SYBR-green based real-time qPCR approach in peripheral blood samples. Combined bisulfite restriction analysis and methylation-specific PCR were used to study promoter CpG island methylation. Further, the effect of homocysteine on BNIP3 gene expression was studied in human aortic endothelial cells in vitro. CAD cases exhibited upregulation of BNIP3, downregulation of EC-SOD and GSTP1. Hypomethylation of BNIP3 and hypermethylation of EC-SOD were observed in CAD cases. The expression of BNIP3 was positively correlated with homocysteine, MDA, protein carbonyls, and methylene tetrahydrofolate reductase C677T, while showing inverse association with cytosolic serine hydroxymethyl transferase C1420T. The expressions of EC-SOD and GSTP1 showed positive association with thymidylate synthase (TYMS) 2R3R, while inverse association with MDA, protein carbonyls, and methionine synthase reductase (MTRR) A66G. In vitro analysis showed homocysteine-dependent upregulation of BNIP3. The results of this study suggest that the aberrations in one-carbon metabolism appear to induce altered gene expression of EC-SOD, GSTP1, and BNIP3, and thus contribute to the increased oxidative stress and increased susceptibility to CAD.
authors.affiliation: Department of Clinical Pharmacology & Therapeutics, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, 500082, Andhra Pradesh, India.
authors.forename: Sana Venkata Vijaya
authors.initials: SV
authors.lastname: Lakshmi
authors.forename: Shaik Mohammad
authors.initials: SM
authors.lastname: Naushad
authors.forename: Cheruku Apoorva
authors.initials: CA
authors.lastname: Reddy
authors.forename: Kankanala
authors.initials: K
authors.lastname: Saumya
authors.forename: Damera Seshagiri
authors.initials: DS
authors.lastname: Rao
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D000077209:Decitabine; D042783:Endothelial Cells / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D012696:Glycine Hydroxymethyltransferase / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000378:metabolism; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics*; D011401:Promoter Regions, Genetic; D050050:Protein Carbonylation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics*; D055815:Young Adult
chemical_list: C090121:BNIP3 protein, human; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D006710:Homocysteine; C012589:trichostatin A; D008315:Malondialdehyde; D000077209:Decitabine; D005492:Folic Acid; C441642:SOD3 protein, human; D013482:Superoxide Dismutase; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D012696:Glycine Hydroxymethyltransferase; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D001374:Azacitidine