Skip to main content
NCBI home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;9(1):153–159. doi: 10.1111/j.1582-4934.2005.tb00345.x

Genomic rearrangements on VCAM1, SELE, APEG1 and AIF1 loci in atherosclerosis

D A Arvanitis 1,2, G A Flouris 1, D A Spandidos 1,✉
PMCID: PMC6741330  PMID: 15784173

Abstract

The inflammatory nature of atherosclerosis has been well established. However, the initial steps that trigger this reponse in the arterial intima remain obscure. Previous studies reported a significant rate of genomic alterations in human atheromas. The accumulation of genomic rearrangements in vascular endothelium and smooth muscle cells may be important for disease development. To address this issue, 78 post‐mortem obtained aortic atheromas were screened for microsatellite DNA alterations versus correspondent venous blood. To evaluate the significance of these observations, 33 additional histologically normal aortic specimens from age and sex‐matched cases were examined. Loss of heterozygosity (LOH) was found in 47,4% of the cases and in 18,2% of controls in at least one locus. The LOH occurrence in aortic tissue is associated to atherosclerosis risk (OR 4,06,95% CI 1,50 to 10,93). Significant genomic alterations were found on 1p32‐p31, 1q22‐q25, 2q35 and 6p21.3 where VCAM1, SELE, APEG1 and AIF1 genes have been mapped respectively. Our data implicate somatic DNA rearrangements, on loci associated to leukocyte adhesion, vascular smooth muscle cells growth, differentiation and migration, to atherosclerosis development as an inflammatory condition.

Keywords: inflammation, microsatellite DNA, loss of heterozygosity

References

  • 1. Ross R., Atherosclerosis: current understanding of mechanisms and future strategies in therapy, Transplant. Proc., 25: 2041–2043, 1993. [PubMed] [Google Scholar]
  • 2. Ross R., Atherosclerosis‐an inflammatory disease, N. Engl. J. Med., 340: 115–126, 1999. [DOI] [PubMed] [Google Scholar]
  • 3. Lusis A.J., Atherosclerosis, Nature, 407: 233–241, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Clinton S.K., Underwood R., Hayes L., Sherman M.L., Kufe D.W., Libby P., Macrophage colony‐stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis, Am. J. Pathol., 140: 301–316, 1992. [PMC free article] [PubMed] [Google Scholar]
  • 5. Fuhrman B., Brook G.J., Aviram M., Proteins derived from platelet alpha granules modulate the uptake of oxidized low density lipoprotein by macrophages, Biochim. Biophys. Acta., 1127: 15–21, 1992. [DOI] [PubMed] [Google Scholar]
  • 6. Pomerantz K.B., Hajjar D.P., Levi R., Gross S.S., Cholesterol enrichment of arterial smooth muscle cells upregulates cytokine‐induced nitric oxide synthesis, Biochem. Biophys. Res. Commun., 191: 103–109, 1993. [DOI] [PubMed] [Google Scholar]
  • 7. Andreassi M.G., Coronary atherosclerosis and somatic mutations: an overview of the contributive factors for oxidative DNA damage, Mutat. Res., 543: 67–86, 2003. [DOI] [PubMed] [Google Scholar]
  • 8. Shih J.C., Pyrzak R., Guy J.S., Discovery of noninfectious viral genes complementary to Marek's disease herpes virus in quail susceptible to cholesterol‐induced atherosclerosis, J. Nutr., 119: 294–298, 1989. [DOI] [PubMed] [Google Scholar]
  • 9. Grayston J.T., Kuo C.C., Campbell L.A., Benditt E.P., Chlamydia pneumoniae, strain TWAR and atherosclerosis, Eur. Heart. J., 14: 66–71, 1993. [PubMed] [Google Scholar]
  • 10. Stone P.H., Coskun A.U., Yeghiazarians Y., Kinlay S., Popma J.J., Kuntz R.E., Feldman C.L., Prediction of sites of coronary atherosclerosis progression: In vivo profiling of endothelial shear stress, lumen, and outer vessel wall characteristics to predict vascular behavior, Curr. Opin. Cardiol., 18: 458–470, 2003. [DOI] [PubMed] [Google Scholar]
  • 11. Ohki R., Yamamoto K., Mano H., Lee R.T., Ikeda U., Shimada K., Identification of mechanically induced genes in human monocytic cells by DNA microarrays, J. Hypertens., 20: 685–691, 2002. [DOI] [PubMed] [Google Scholar]
  • 12. Spandidos D.A., Ergazaki M., Arvanitis D., Kiaris H., Microsatellite instability in human atherosclerotic plaques, Biochem. Biophys. Res. Commun., 220: 137–140, 1996. [DOI] [PubMed] [Google Scholar]
  • 13. De Flora S., Izzotti A., Walsh D., Degan P., Petrilli G.L., Lewtas J., Molecular epidemiology of atherosclerosis, FASEB J., 11: 1021–1031, 1997. [PubMed] [Google Scholar]
  • 14. Flouris G.A., Arvanitis D.A., Parissis J.T., Arvanitis D.L., Spandidos D.A., Loss of heterozygosity in DNA mismatch repair genes in human atherosclerotic plaques, Mol. Cell. Biol. Res. Commun., 4: 62–65, 2000. [DOI] [PubMed] [Google Scholar]
  • 15. Binkova B., Strejc P., Boubelik O., Stavkova Z., Chvatalova I., Sram R.J., DNA adducts and human atherosclerotic lesions, Int. J. Hyg. Environ. Health., 204: 49–54, 2001. [DOI] [PubMed] [Google Scholar]
  • 16. Izzotti A., Cartiglia C., Lewtas J., De Flora S., Increased DNA alterations in atherosclerotic lesions of individuals lacking the GSTM1 genotype, FASEB J., 15: 752–757, 2001. [DOI] [PubMed] [Google Scholar]
  • 17. Miniati P., Sourvinos G., Michalodimitrakis M., Spandidos D.A., Loss of heterozygosity on chromosomes 1, 2, 8, 9 and 17 in cerebral atherosclerotic plaques, Int. J. Biol. Markers, 16: 167–171, 2001. [DOI] [PubMed] [Google Scholar]
  • 18. Botto N., Rizza A., Colombo M.G., Mazzone A.M., Manfredi S., Masetti S., Clerico A., Biagini A., Andreassi M.G., Evidence for DNA damage in patients with coronary artery disease, Mutat. Res., 493: 23–30, 2001. [DOI] [PubMed] [Google Scholar]
  • 19. Botto N., Masetti S., Petrozzi L., Vassalle C., Manfredi S., Biagini A., Andreassi M.G., Elevated levels of oxidative DNA damage in patients with coronary artery disease, Coron. Artery. Dis., 13: 269–274, 2002. [DOI] [PubMed] [Google Scholar]
  • 20. Martinet W., Knaapen M.W., De Meyer G.R., Herman A.G., Kockx M.M., Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques, Circulation, 106: 927–932, 2002. [DOI] [PubMed] [Google Scholar]
  • 21. Hatzistamou J., Kiaris H., Ergazaki M., Spandidos D.A., Loss of heterozygosity and microsatellite instability in human atherosclerotic plaques, Biochem. Biophys. Res. Commun., 225: 186–190, 1996. [DOI] [PubMed] [Google Scholar]
  • 22. Chung I.M., Schwartz S.M., Murry C.E., Clonal architecture of normal and atherosclerotic aorta: implications for atherogenesis and vascular development, Am. J. Pathol., 152: 913–923, 1998. [PMC free article] [PubMed] [Google Scholar]
  • 23. Mulvihill E.R., Jaeger J., Sengupta R., Ruzzo W.L., Reimer C., Lukito S., Schwartz S.M., Atherosclerotic plaque smooth muscle cells have a distinct phenotype, Arterioscler. Thromb. Vasc. Biol., 24: 1283–1289, 2004. [DOI] [PubMed] [Google Scholar]
  • 24. Arvanitis D.A., Goumenou A.G., Matalliotakis I.M., Koumantakis E.E., Spandidos D.A., Low‐penetrance genes are associated with increased susceptibility to endometriosis, Fertil. Steril., 76: 1202–1206, 2001. [DOI] [PubMed] [Google Scholar]
  • 25. Kiaris H., Hatzistamou J., Spandidos D.A., Instability at the H‐ras minisatellite in human atherosclerotic plaques, Atherosclerosis, 125: 47–51, 1996. [DOI] [PubMed] [Google Scholar]
  • 26. Grati F.R., Ghilardi G., Sirchia S.M., Massaro F., Cassani B., Scorza R., De Andreis C., Sironi E., Simoni G., Loss of heterozygosity of the NOS3 dinucleotide repeat marker in atherosclerotic plaques of human carotid arteries, Atherosclerosis, 159: 261–267, 2001. [DOI] [PubMed] [Google Scholar]
  • 27. Spandidos D.A., Sourvinos G., Kiaris H., Tsamparlakis J., Microsatellite instability and loss of heterozygosity in human pterygia, Br. J. Ophthalmol., 81: 493–496, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Zachos G., Koumantaki E., Vareltzidis A., Spandidos D.A., Evidence for loss of heterozygosity in human psoriatic lesions, Br. J. Dermatol., 139: 974–977, 1998. [DOI] [PubMed] [Google Scholar]
  • 29. Davies M.J., Turner J.G., Vives‐Bauza C., Rumsby P.C., Investigation of mutant frequency at the HPRT locus and changes in microsatellite sequences in healthy young adults, Mutat. Res., 431: 317–323, 1999. [DOI] [PubMed] [Google Scholar]
  • 30. Goumenou A.G., Arvanitis D.A., Matalliotakis I.M., Koumantakis E.E., Spandidos D.A., Microsatellite DNA assays reveal an allelic imbalance in p16(Ink4), GALT, p53, and APOA2 loci in patients with endometriosis, Fertil. Steril., 75: 160–165, 2001. [DOI] [PubMed] [Google Scholar]
  • 31. Paraskakis E., Sourvinos G., Passam F., Tzanakis N., Tzortzaki E.G., Zervou M., Spandidos D., Siafakas N.M., Microsatellite DNA instability and loss of heterozygosity in bronchial asthma, Eur. Respir. J., 22: 951–955, 2003. [DOI] [PubMed] [Google Scholar]
  • 32. Demopoulos K., Arvanitis D.A., Vassilakis D.A., Siafakas N.M., Spandidos D.A., MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis, J. Cell. Mol. Med., 6: 215–222, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Arvanitis D.A., Papadakis E., Zafiropoulos A., Spandidos D.A., Fractional allele loss is a valuable marker for human lung cancer detection in sputum, Lung. Cancer., 40: 55–66, 2003. [DOI] [PubMed] [Google Scholar]
  • 34. Manolaraki M.M., Arvanitis D.A., Sourvinos G., Sifakis S., Koumantakis E., Spandidos D.A., Frequent loss of heterozygosity in chromosomal region 9pter‐p13 in tumor biopsies and cytological material of uterine cervical cancer, Cancer. Lett., 176: 175–181, 2002. [DOI] [PubMed] [Google Scholar]
  • 35. Pepinsky B., Hession C., Chen L.L., Moy P., Burkly L., Jakubowski A., Chow E.P., Benjamin C., Chi‐Rosso G., Luhowskyj S., et al., Structure/function studies on vascular cell adhesion molecule‐1, J. Biol. Chem., 267: 17820–17826, 1992. [PubMed] [Google Scholar]
  • 36. Cybulsky M.I., Iiyama K., Li H., Zhu S., Chen M., Iiyama M., Davis V., Gutierrez‐Ramos J.C., Connelly P.W., Milstone D.S., A major role for VCAM‐1, but not ICAM‐1, in early atherosclerosis, J. Clin. Invest., 107: 1255–1262, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Dansky H.M., Barlow C.B., Lominska C., Sikes J.L., Kao C., Weinsaft J., Cybulsky M.I., Smith J.D., Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule‐1 gene dosage, Arterioscler. Thromb. Vasc. Biol., 21: 1662–1667, 2001. [DOI] [PubMed] [Google Scholar]
  • 38. Bevilacqua M.P., Nelson R.M., Mannori G., Cecconi O., Endothelial‐leukocyte adhesion molecules in human disease, Annu. Rev. Med., 45: 361–378, 1994. [DOI] [PubMed] [Google Scholar]
  • 39. Blann A.D., Lip G.Y., Coronary risk factors, endothelial function, and atherosclerosis: a review, Clin. Cardiol., 20: 822, 824, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Incalcaterra E., Hoffmann E., Averna M.R., Caimi G., Genetic risk factors in myocardial infarction at young age, Minerva Cardioangiol., 52: 287–312, 2004. [PubMed] [Google Scholar]
  • 41. Hsieh C.M., Yet S.F., Layne M.D., Watanabe M., Hong A.M., Perrella M.A., Lee M.E., Genomic cloning and promoter analysis of aortic preferentially expressed gene‐1. Identification of a vascular smooth muscle‐specific promoter mediated by an E box motif, J. Biol. Chem., 274: 14344–14351, 1999. [DOI] [PubMed] [Google Scholar]
  • 42. Hsieh C.M., Fukumoto S., Layne M.D., Maemura K., Charles H., Patel A., Perrella M.A., Lee M.E., Striated muscle preferentially expressed genes alpha and beta are two serine/threonine protein kinases derived from the same gene as the aortic preferentially expressed gene‐1, J. Biol. Chem., 275: 36966–36973, 2000. [DOI] [PubMed] [Google Scholar]
  • 43. Autieri M.V., Kelemen S.E., Wendt K.W., AIF‐1 is an actin‐polymerizing and Rac1‐activating protein that promotes vascular smooth muscle cell migration, Circ. Res., 92: 1107–1114, 2003. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES