DNA methylation status of the cell proliferation genes in atherosclerosis
Abstract
The purpose of this study was to identify the features of methylation status of genes whose products are involved in the cell proliferation in vascular tissues of patients with atherosclerosis. We tested the vascular samples from carotid arteries, internal mammary arteries and saphenous veins, which differ in their morphological and functional characteristics and the degree of susceptibility to pathology. DNA methylation profiling was performed by using the microarray «Infinium Human-Methylation27 BeadChip» («Illumina», USA), methylation-sensitive polymerase chain reaction and methylation-specific PCR. For the first time we identified 45 CpG-sites of 36 genes with differential DNA methylation between vascular tissues. The most pronounced differences in the DNA methylation level were registered for CpG-dinucleotides of genes ALOX12, CARD11, DAB2IP, PTPRC, RA-SIP1, THRB, TLR4, TNFRSF9 and WNT16. Our data do not support the hypothesis of epigenetic dysregulation of cell-cycle genes (CDKN2A (p16INK4a and p14ARF), CDKN2B (p15INK4b)) in atherosclerosis.
About the Authors
M. S. Nazarenko
RAMS
Russian Federation
Russian Federation
SB RAMS
Federal state budget institution "Research Institute of Medical Genetics"
634050
st. River embankment Ears, 10
Tomsk
A. V. Markov
RAMS
Russian Federation
Russian Federation
SB RAMS
Federal state budget institution "Research Institute of Medical Genetics"
634050
st. River embankment Ears, 10
Tomsk
I. N. Lebedev
RAMS
Russian Federation
Russian Federation
SB RAMS
Federal state budget institution "Research Institute of Medical Genetics"
634050
st. River embankment Ears, 10
Tomsk
A. A. Sleptsov
RAMS
Russian Federation
Russian Federation
SB RAMS
Federal state budget institution "Research Institute of Medical Genetics"
634050
st. River embankment Ears, 10
Tomsk
A. V. Frolov
RAMS
Russian Federation
Russian Federation
SB RAMS
Federal state budget institution "Research Institute of Complex Problems of Cardiovascular Diseases"
650002
Pine Boulevard, 6
Kemerovo
O. L. Barbarash
RAMS
Russian Federation
Russian Federation
SB RAMS
Federal state budget institution "Research Institute of Complex Problems of Cardiovascular Diseases"
650002
Pine Boulevard, 6
Kemerovo
L. S. Barbarash
RAMS
Russian Federation
Russian Federation
SB RAMS
Federal state budget institution "Research Institute of Complex Problems of Cardiovascular Diseases"
650002
Pine Boulevard, 6
Kemerovo
V. P. Puzyrev
RAMS
Russian Federation
Russian Federation
SB RAMS
Federal state budget institution "Research Institute of Medical Genetics"
References
1. Schnabel R. B., Baccarelli A., Lin H. et al. Next steps in cardiovascular disease genomic research-sequencing, epigenetics, and transcriptomics // Clin. Chem. 2012. Vol. 58. P. 113–126.
2. Turunen M. P., Aavik E., Yla-Herttuala S. Epigenetics and atherosclerosis // Biochim. Biophys. Acta. 2009. Vol. 1790. P. 886–891.
3. Castillo-Diaz S. A., Garay-Sevilla M. E., Hernandez-Gonzalez M. A. et al. Extensive demethylation of normally hypermethylated CpG islands occurs in human atherosclerotic arteries // Int. J. Mol. Med. 2010. Vol. 26. P. 691–700.
4. Назаренко М. С. Профиль метилирования ДНК в области атеросклеротических бляшек человека / М. С. Назаренко // Молекулярная биология. – 2011. – Т. 45. – С. 610–616.
5. Hiltunen M. O., Turunen M. P., Hakkinen T. P. et al. DNA hypomethylation and methyltransferase expression in atherosclerotic lesions // Vasc. Med. 2002. Vol. 7. P. 5–11.
6. Post W. S., Goldschmidt-Clermont P. J., Wilhide C. C. et al. Methylation of the estrogen receptor gene is associated with aging and atherosclerosis in the cardiovascular system // Cardiovasc. Res. 1999. Vol. 43. P. 985–991.
7. Kim J., Kim J. Y., Song K. S. et al. Epigenetic changes in estrogen receptor beta gene in atherosclerotic cardiovascular tissues and in-vitro vascular senescence // Biochim. Biophys. Acta. 2007. Vol. 1772. P. 72–80.
8. Zhu S., Goldschmidt-Clermont P. J., Dong C. Inactivation of monocarboxylate transporter MCT3 by DNA methylation in atherosclerosis // Circulation. 2005. Vol. 112. P. 1353–1361.
9. Zawadzki C., Chatelain N., Delestre M. et al. Tissue factor pathway inhibitor-2 gene methylation is associated with low expression in carotid atherosclerotic plaques // Atherosclerosis. 2009. Vol. 204. P. e4–e14.
10. Wellcome Trust Case Control Consortium. Genomewide association study of 14.000 cases of seven common diseases and 3.000 shared controls // Nature. 2007. Vol. 447. P. 661–678.
11. Helgadottir A., Thorleifsson G., Manolescu A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction // Science. 2007. Vol. 316. P. 1491–1493.
12. McPherson R., Pertsemlidis A., Kavaslar N. et al. A common allele on chromosome 9 associated with coronary heart disease // Science. 2007. Vol. 316. P. 1488–1491.
13. Samani N. J., Erdmann J., Hall A. S. et al. Genomewide association analysis of coronary artery disease // N. Engl. J. Med. 2007. Vol. 357. P. 443–453.
14. Cunnington M. S., Keavney B. Genetic mechanisms mediating atherosclerosis susceptibility at the chromosome 9p21 locus // Curr. Atheroscler. Rep. 2011. Vol. 13. P. 193–201.
15. Popov N., Gil J. Epigenetic regulation of the INK4b-ARF-INK4a locus: in sickness and in health // Epigenetics. 2010. Vol. 5. P. 685–690.
16. Gonzalez-Navarro H., Abu Nabah Y. N., Vinue A. et al. p19(ARF) deficiency reduces macrophage and vascular smooth muscle cell apoptosis and aggravates atherosclerosis // J. Am. Coll. Cardiol. 2010. V. 55. P. 2258–2268.
17. Покровский А. В. Показания к хирургическому лечению сосудисто-мозговой недостаточности у больных с окклюзирующими поражениями брахиоцефальных сосудов / А. В. Покровский [и др.] // Невропатология и психиатрия. –1977. – С. 1789–1797.
18. Bibikova M., Le J., Barnes B. et al. Genome-wide DNA methylation profiling using Infinium assay // Epigenomics. 2009. Vol. 1. P. 177–200.
19. Benjamini Y., Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing // J. R. Stat. Soc. Series B Stat. Methodol. 1995. Vol. 57. P. 289–300.
20. Землякова В. В. Сравнительный анализ аномального метилирования CpG-островков, расположенных в промоторных областях генов Р16/CDKN2A и P14ARF, при немелкоклеточном раке легкого и остром лимфобластном лейкозе / В. В. Землякова [и др.] // Мол. биол. – 2004. – Т. 38. – С. 966–972.
21. Amatya V. J., Takeshima Y., Inai K. Methylation of p14(ARF) gene in meningiomas and its correlation to the p53 expression and mutation // Mod. Pathol. 2004. Vol. 17. P. 705–10.
22. Herman J. G., Graff J. R., Myohanen S. et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands // Proc. Natl. Acad. Sci. USA. 1996. Vol. 93. P. 9821–9826.
23. Fuster J. J., Fernandez P., Gonzalez-Navarro H. et al. Control of cell proliferation in atherosclerosis: insights from animal models and human studies // Cardiovasc. Res. 2010. Vol. 86. P. 254–264.
24. Gertow K., Nobili E., Folkersen L. et al. 12- and 15-lipoxygenases in human carotid atherosclerotic lesions: associations with cerebrovascular symptoms // Atherosclerosis. 2011. Vol. 215. P. 411–416.
25. Xu K., Sacharidou A., Fu S. et al. Blood vessel tubulogenesis requires Rasip1 regulation of GTPase signaling // Dev. Cell. 2011. Vol. 20. P. 526–539.
26. Ikram M. K., Sim X., Jensen R. A. et al. Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo // PLoS Genet. 2010. Vol. 6. P. e1001184.
27. den Dekker W. K., Cheng C., Pasterkamp G., Duckers H. J. Toll like receptor 4 in atherosclerosis and plaque destabilization // Atherosclerosis. 2010. Vol. 209. P. 314–320.
28. Moghimpour Bijani F., Vallejo J. G., Rezaei N. Tolllike Receptor Signaling Pathways in Cardiovascular Diseases: Challenges and Opportunities // Int. Rev. Immunol. 2012. Vol. 31. P. 379–395.
29. Olofsson P. S., Soderstrom L. A., Wagsater D. et al. CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice // Circulation. 2008. Vol. 117. P. 1292–1301.
30. Yan J., Gong J., Liu P. et al. Positive correlation between CD137 expression and complex stenosis morphology in patients with acute coronary syndromes // Clin. Chim. Acta. 2011. Vol. 412. P. 993–998.
31. Jeon H. J., Choi J. H., Jung I. H. et al. CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice // Circulation. 2010. Vol. 121. P. 1124–1133.
32. Holdt L. M., Sass K., Gabel G. Expression of Chr9p21 genes CDKN2B (p15INK4b), CDKN2A (p16INK4a, p14ARF) and MTAP in human atherosclerotic plaque // Atherosclerosis. 2011. Vol. 214. Р. 264–270.
Review
For citations:
Nazarenko M.S., Markov A.V., Lebedev I.N., Sleptsov A.A., Frolov A.V., Barbarash O.L., Barbarash L.S., Puzyrev V.P. DNA methylation status of the cell proliferation genes in atherosclerosis. Ateroscleroz. 2013;9(1):5-13. (In Russ.)
Views:
232
Email this article 