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Oxidative stress in coronary artery disease: epigenetic perspective

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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.

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Abbreviations

CAD:

Coronary artery disease

BNIP3:

Bcl2/adenovirus E1B interacting protein-3

EC-SOD:

Extracellular superoxide dismutase

GSTP1:

Glutathione-S-transferase pi

8-OxodG:

8-Oxo-2′-deoxyguanosine

MDA:

Malondialdehyde

HAECs:

Human aortic endothelial cells

DEPC:

Diethylpyrocarbonate

COBRA:

Combined bisulfite restriction analysis

MSP:

Methylation-specific PCR

ROS:

Reactive oxygen species

EBM:

Endothelial basal medium

FBS:

Foetal bovine serum

GCPII C1561T:

Glutamate carboxypeptidase II

MTHFR C677T:

Methylene tetrahydrofolate homocysteine methyltransferase

MTRR A66G:

Methionine synthase reductase

cSHMT C1420T:

Cytosolic serine hydroxymethyl transferase

TYMS:

Thymidylate synthase 5′-UTR 28 bp tandem repeat

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Acknowledgments

We acknowledge Council of Scientific and Industrial Research (CSIR), New Delhi for providing Senior Research Fellowship (SRF) to SVV. VKK and KS are recipients of Ramanujan Fellowship awarded by Department of Science and Technology, Government of India.

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Authors and Affiliations

  1. Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Panjagutta, Hyderabad, 500082, Andhra Pradesh, India

    Sana Venkata Vijaya Lakshmi, Shaik Mohammad Naushad, Cheruku Apoorva Reddy, Kankanala Saumya & Vijay Kumar Kutala

  2. Department of Cardiology, Nizam’s Institute of Medical Sciences, Hyderabad, India

    Damera Seshagiri Rao

  3. Chemical Biology Division, Indian Institute of Chemical Technology, Hyderabad, India

    Srigiridhar Kotamraju

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  1. Sana Venkata Vijaya Lakshmi
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Correspondence to Vijay Kumar Kutala.

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Lakshmi, S.V.V., Naushad, S.M., Reddy, C.A. et al. Oxidative stress in coronary artery disease: epigenetic perspective. Mol Cell Biochem 374, 203–211 (2013). https://doi.org/10.1007/s11010-012-1520-7

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  • DOI: https://doi.org/10.1007/s11010-012-1520-7

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