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Compilation and Analysis of Atherosclerosis Gene Expression Data

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DOI: 10.4236/abc.2015.52011    3,811 Downloads   4,530 Views  


The objective of this project was to search for consensus in differential gene expression data and in regulation of differentially expressed genes among DNA microarray studies of atherosclerotic vessels and plaque. Seventeen DNA microarray studies of atherosclerosis were analyzed. Only 19 genes were found to be differentially expressed in 3 or more of the studies. The nineteen genes belong to classic gene ontologies known to be involved in atherosclerosis: immunity and defense, metabolism, proteases, receptors, and signal transduction. Four bioinformatics programs (TRED, rVISTA, JASPAR, and Ariadne Pathways) were used to further analyze the promoter regions and common upstream regulators of the 19 genes. Twelve of the genes shared nine common upstream regulators, many of them known to affect atherosclerosis, and one possible new pathway was identified that may be involved in this disease.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Booze, M. and Eyster, K. (2015) Compilation and Analysis of Atherosclerosis Gene Expression Data. Advances in Biological Chemistry, 5, 142-150. doi: 10.4236/abc.2015.52011.


[1] Yauk, C.L. and Berndt, M.L. (2007) Review of the Literature Examining the Correlation among DNA Microarray Technolo-gies. Environmental and Molecular Mutagenesis, 48, 380-394.
[2] Faber, B.C., Heeneman, S., Daemen, M.J. and Cleutjens, K.B. (2002) Genes Potentially Involved in Plaque Rupture. Current Opinion in Lipidology, 13, 545-552.
[3] Hiltunen, M.O., Tuomisto, T.T., Niemi, M., Brasen, J.H., Rissanen, T.T., Toronen, P., Vajanto, I. and Yla-Herttuala, S. (2002) Changes in Gene Expression in Atherosclerotic Plaques Analyzed Using DNA Array. Atherosclerosis, 165, 23- 32.
[4] Martinet, W., Schrijvers, D.M., De Meyer, G.R., Thielemans, J., Knaapen, M.W., Herman, A.G. and Kockx, M.M. (2002) Gene Expression Profiling of Apoptosis-Related Genes in Human Atherosclerosis: Upregulation of Death-As- sociated Protein Kinase. Thrombosis, and Vascular Biology, 22, 2023-2029.
[5] Randi, A.M., Biguzzi, E., Falciani, F., Merlini, P., Blakemore, S., Bramucci, E., Lucreziotti, S., Lennon, M., Faioni, E.M., Ardissino, D. and Mannucci, P.M. (2003) Identifica-tion of Differentially Expressed Genes in Coronary Atherosclerotic Plaques from Patients with Stable or Unstable Angina by cDNA Array Analysis. Journal of Thrombosis and Haemostasis, 1, 829-835.
[6] Tuomisto, T.T., Korkeela, A., Rutanen, J., Viita, H., Brasen, J.H., Riekkinen, M.S., Rissanen, T.T., Karkola, K., Kiraly, Z., Kolble, K. and Yla-Herttuala, S. (2003) Gene Expression in Macrophage-Rich Inflammatory Cell Infiltrates in Human Atherosclerotic Lesions as Studied by Laser Microdissection and DNA Array: Overexpression of HMG-CoA Reductase, Colony Stimulating Factor Receptors, CD11A/CD18 Integrins, and Interleukin Receptors. Thrombosis, and Vascular Biology, 23, 2235-2240.
[7] Woodside, K.J., Hernandez, A., Smith, F.W., Xue, X.Y., Hu, M., Daller, J.A. and Hunter, G.C. (2003) Differential Gene Expression in Primary and Recurrent Carotid Stenosis. Bio-chemical and Biophysical Research Communications, 302, 509-514.
[8] King, J.Y., Ferrara, R., Tabibiazar, R., Spin, J.M., Chen, M.M., Kuchinsky, A., Vailaya, A., Kincaid, R., Tsalenko, A., Deng, D.X., Connolly, A., Zhang, P., Yang, E., Watt, C., Yakhini, Z., Ben-Dor, A., Adler, A., Bruhn, L., Tsao, P., Quertermous, T. and Ashley, E.A. (2005) Pathway Analysis of Coronary Atherosclerosis. Physiological Genomics, 23, 103-118.
[9] Lutgens, E., Faber, B., Schapira, K., Evelo, C.T., van Haaften, R., Heeneman, S., Cleutjens, K.B., Bijnens, A.P., Beckers, L., Porter, J.G., Mackay, C.R., Rennert, P., Bailly, V., Jarpe, M., Dolinski, B., Koteliansky, V., de Fougerolles, T. and Daemen, M.J. (2005) Gene Profiling in Atherosclerosis Re-veals a Key Role for Small Inducible Cytokines: Validation Using a Novel Monocyte Chemoattractant Protein Monoclonal Antibody. Circulation, 111, 3443-3452.
[10] Papaspyridonos, M., Smith, A., Burnand, K.G., Taylor, P., Padayachee, S., Suckling, K.E., James, C.H., Greaves, D.R. and Patel, L. (2006) Novel Candidate Genes in Unstable Areas of Human Atherosclerotic Plaques. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 1837-1844.
[11] Dahl, T.B., Yndestad, A., Skjelland, M, Oie, E., Dahl, A., Michelsen, A., Damas, J.K., Tunheim, S.H., Ueland, T., Smith, C., Bendz, B., Tonstad, S, Gullestad, L., Froland, S.S., Krohg-Sorensen, K., Russell, D., Aukrust, P. and Halvorsen, B. (2007) Increased Expression of Visfatin in Macrophages of Human Unstable Carotid and Coronary Atherosclerosis: Possible Role in Inflammation and Plaque Destabilization. Circulation, 115, 972-980.
[12] Volger, O.L., Fledderus, J.O., Kisters, N., Fontijn, R.D., Moerland, P.D., Kuiper, J., van Berkel, T.J., Bijnens, A.P., Daemen, M.J., Pannekoek, H. and Horrevoets, A.J. (2007) Distinctive Expression of Chemokines and Transforming Growth Factor-Beta Signaling in Human Arterial Endothelium during Atherosclerosis. American Journal of Pathology, 171, 326-337.
[13] Evans, D.C., Sileshi, B., Zakaria, A.M., Giangiacomo, D., Manson, R.J. and Lawson, J.H. (2008) Genomic Modeling of Atherosclerosis in Peripheral Arterial Disease and Its Variant Phenotype in Patients with Diabetes. Vascular, 16, 225-235.
[14] Fu, S., Zhao, H., Shi, J., Abzhanov, A., Crawford, K., Ohno-Machado, L., Zhou, J., Du, Y., Kuo, W.P., Zhang, J., Jiang, M. and Jin, J.G. (2008) Peripheral Arterial Occlusive Disease: Global Gene Expression Analyses Suggest a Major Role for Immune and Inflammatory Responses. BMC Genomics, 9, 369.
[15] Murillo, C.A., Woodside, K.J., Guo, Q., Zhang, S., O’Connor, K.L. and Hunter, G.C. (2009) Integrin and Matrix Metalloproteinase Expression in Human Carotid Plaque. Journal of Surgical Research, 155, 157-164.
[16] Fam, N.P., Arab, S., Billia, F., Han, R., Proteau, G., Latter, D., Errett, L., Bonneau, D., Dunne, R., Liu, P.P. and Stewart, D.J. (2010) Increased Myocardial Expression of Angiopoietin-2 in Patients Undergoing Urgent Surgical Revascularization for Acute Coronary Syndromes. Canadian Journal of Cardiology, 26, 365-370.
[17] Eyster, K.M., Appt, S.E., Mark-Kappeler, C.J., Chalpe, A., Register, T.C. and Clarkson, T.B. (2011) Gene Expression Signatures Differ with Extent of Atherosclerosis in Monkey Iliac Artery. Menopause, 18, 1087-1095.
[18] Perisic, L., Hedin, E., Razuvaev, A., Lengquist, M., Osterholm, C., Folkersen, L., Gillgren, P., Paulsson-Berne, G., Ponten, F., Odeberg, J. and Hedin, U. (2013) Profiling of Atherosclerotic Lesions by Gene and Tissue Microarrays Reveals PCSK6 as a Novel Protease in Unstable Carotid Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 33, 2432-2443.
[19] Libby, P., Lichtman, A.H. and Hansson, G.K. (2013) Immune Effector Mechanisms Implicated in Atherosclerosis: From Mice to Humans. Immunity, 38, 1092-1104.
[20] Krahmer, N., Farese Jr., R.V. and Walther, T.C. (2013) Balancing the Fat: Lipid Droplets and Human Disease. EMBO Molecular Medicine, 5, 905-915.
[21] Hopkins, P.N. (2013) Molecular Biology of Atherosclerosis. Physi-ological Reviews, 93, 1317-1542.
[22] Weber, K.S., Nelson, P.J., Grone, H.J. and Weber, C. (1999) Expression of CCR2 by Endothelial Cells: Implications for MCP-1 Mediated Wound Injury Repair and in Vivo Inflammatory Activation of Endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology, 19, 2085-2093.
[23] Nakamura, T., Hinagata, J., Tanaka, T., Imanishi, T., Wada, Y., Kodama, T. and Doi, T. (2002) HSP90, HSP70, and GAPDH Directly Interact with the Cytoplasmic Domain of Macrophage Scavenger Receptors. Biochemical and Biophysical Research Communications, 290, 858-864.
[24] Baitsch, D., Bock, H.H., Engel, T., Telgmann, R., Muller-Tidow, C., Varga, G., Bot, M., Herz, J., Robenek, H., von Eckardstein, A. and Nofer, J.R. (2011) Apolipoprotein E Induces Anti-inflammatory Phenotype in Macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 1160-1168.
[25] Zhang, W.Y., Gaynor, P.M. and Kruth, H.S. (1996) Apolipo-protein E Produced by Human Monocyte-Derived Macrophages Mediates Cholesterol Efflux That Occurs in the Absence of Added Cholesterol Acceptors. Journal of Biological Chemistry, 271, 28641-28646.
[26] Makowski, L., Boord, J.B., Maeda, K., Babaev, V.R., Uysal, K.T., Morgan, M.A., Parker, R.A., Suttles, J., Fazio, S., Hotamisligil, G.S. and Linton, M.F. (2001) Lack of Macrophage Fat-ty-Acid-Binding Protein aP2 Protects Mice Deficient in Apolipoprotein E against Atherosclerosis. Nature Medicine, 7, 699-705.
[27] Furuhashi, M., Ishimura, S., Ota, H. and Miura, T. (2011) Lipid Chaperones and Metabolic Inflammation. International Journal of Inflammation, 2011, Article ID: 642612.
[28] Sukhova, G.K., Shi, G.P., Simon, D.I., Chapman, H.A. and Libby, P. (1998) Expression of the Elastolytic Cathepsins S and K in Human Atheroma and Regulation of Their Production in Smooth Muscle Cells. Journal of Clinical Investigation, 102, 576-583.
[29] Taleb, S. and Clement, K. (2007) Emerging Role of Cathepsin S in Obesity and Its Associated Diseases. Clinical Chemical Laboratory Medicine, 45, 328-332.
[30] Newby, A.C., George, S.J., Ismail, Y., Johnson, J.L., Sala-Newby, G.B. and Thomas, A.C. (2009) Vulnerable Atherosclerotic Plaque Metalloproteinases and Foam Cell Phenotypes. Thrombosis and Haemostasis, 101, 1006-1011.
[31] de Nooijer, R., Verkleij, C.J., von der Thusen, J.H., Jukema, J.W., van der Wall, E.E., van Berkel, T.J., Baker, A.H. and Biessen, E.A. (2006) Lesional Overexpression of Matrix Metalloproteinase-9 Promotes Intraplaque Hemorrhage in Advanced Lesions but Not at Earlier Stages of Atherogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 340-346.
[32] Nhan, T.Q., Liles, W.C. and Schwartz, S.M. (2005) Role of Caspases in Death and Survival of the Plaque Macrophage. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 895-903.
[33] Stocker, R. and Perrella, M.A. (2006) Heme Oxygenase-1: A Novel Drug Target for Atherosclerotic Diseases? Circulation, 114, 2178-2189.
[34] Ijas, P., Nuotio, K., Saksi, J., Soinne, L., Saimanen, E., Karjalainen-Lindsberg, M.L., Salonen, O., Sarna, S., Tuimala, J., Kovanen, P.T., Kaste, M. and Lindsberg, P.J. (2007) Microarray Analysis Reveals Overexpression of CD163 and HO-1 in Symptomatic Carotid Plaques. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 154-160.
[35] Ramsis, N., El-Hawary, A.A. and Ismail, E. (1998) Relation between Carotid Intima-Media Thickness, Platelet Surface Activation and Endothelial Cell Markers. Haemostasis, 28, 268-275.
[36] Zhang, K., Huang, X.Z., Li, X.N., Feng, M., Li, L., Cai, X.J., Zhang, C., Liu, X.L., Zhang, M.X., Zhang, Y., Wang, X.L. and Zhang, M. (2012) Interleukin 6 Destabilizes Atherosclerotic Plaques by Downregulating Prolyl-4-Hydroxylase Alpha1 via a Mitogen-Activated Protein Kinase and C-Jun Pathway. Archives of Biochemistry and Biophysics, 528, 127-133.
[37] Senokuchi, T., Matsumura, T., Sakai, M., Matsuo, T., Yano, M., Kiritoshi, S., Sonoda, K., Kukidome, D., Nishikawa, T. and Araki, E. (2004) Extracellular Signal-Regulated Kinase and p38 Mitogen-Activated Protein Kinase Mediate Macrophage Proliferation Induced by Oxidized Low-Density Lipoprotein. Atherosclerosis, 176, 233-245.
[38] Voloshyna, I., Littlefield, M.J. and Reiss, A.B. (2014) Atherosclerosis and Interferon-Gamma: New Insights and Therapeutic Targets. Trends in Cardiovascular Medicine, 24, 45-51.
[39] Schuett, H., Luchtefeld, M., Grothusen, C., Grote, K. and Schieffer, B. (2009) How Much Is Too Much? Interleukin-6 and Its Signalling in Atherosclerosis. Throm-bosis and Haemostasis, 102, 215-222.
[40] Goetze, S., Xi, X.P., Kawano, Y., Kawano, H., Fleck, E., Hsueh, W.A. and Law, R.E. (1999) TNF-Alpha-Induced Migration of Vascular Smooth Muscle Cells Is MAPK Dependent. Hypertension, 33, 183-189.
[41] Watanabe, S., Mu, W., Kahn, A., Jing, N., Li, J.H., Lan, H.Y., Nakagawa, T., Ohashi, R. and Johnson, R.J. (2004) Role of JAK/STAT Pathway in IL-6-Induced Activation of Vascular Smooth Muscle Cells. American Journal of Nephrology, 24, 387-392.
[42] Harvey, E.J., Li, N. and Ramji, D.P. (2007) Critical Role for Casein Kinase 2 and Phosphoinositide-3-Kinase in the Interferon-Gamma-Induced Expression of Monocyte Chemoattractant Protein-1 and Other Key Genes Implicated in Atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 806-812.
[43] Murthy, S., Ryan, A.J. and Carter, A.B. (2012) SP-1 Regulation of MMP-9 Expression Requires Ser586 in the PEST Domain. Biochemical Journal, 445, 229-236.
[44] Wei, M.C., Zong, W.X., Cheng, E.H., Lindsten, T., Panoutsakopoulou, V., Ross, A.J., Roth, K.A., MacGregor, G.R., Thompson, C.B. and Korsmeyer, S.J. (2001) Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death. Science, 292, 727-730.
[45] Liu, J., Thewke, D.P., Su, Y.R., Linton, M.F., Fazio, S. and Sinensky, M.S. (2005) Reduced Macrophage Apoptosis Is Associated with Accelerated Atherosclerosis in Low-Density Lipoprotein Receptor-Null Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 174-179.
[46] Hardwick, S.J., Hegyi, L., Clare, K., Law, N.S., Carpenter, K.L., Mitchinson, M.J. and Skepper, J.N. (1996) Apoptosis in Human Monocyte-Macrophages Exposed to Oxidized Low Density Lipoprotein. The Journal of Pathology, 179, 294-302.<294::AID-PATH590>3.0.CO;2-X
[47] Sata, M. and Walsh, K. (1998) Oxidized LDL Activates Fas-Mediated Endothelial Cell Apoptosis. Journal of Clinical Investigation, 102, 1682-1689.
[48] Loidl, A., Claus, R., Ingolic, E., Deigner, H.P. and Hermetter, A. (2004) Role of Ceramide in Activation of Stress-Associated MAP Kinases by Minimally Modified LDL in Vascular Smooth Muscle Cells. Biochimica et Biophysica Acta, 1690, 150-158.
[49] Schmidt, T., Korner, K., Karsunky, H., Korsmeyer, S., Muller, R. and Moroy, T. (1999) The Activity of the Murine Bax Promoter Is Regulated by Sp1/3 and E-Box Binding Proteins but Not by p53. Cell Death and Differentiation, 6, 873-882.

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