Abstract
We performed a strain intercross between two apoE-deficient mouse strains with a large difference in lesion susceptibility and measured aortic root lesion area in 98 female F2 progeny. Total RNA was prepared from bone marrow-derived macrophages, and RNA from the five mice with the smallest and largest lesions were used for microarray gene expression profiling. Remarkably, approximately 5% of the 12,288 expressed transcripts were differentially expressed in the atherosclerosis-susceptible and atherosclerosis-resistant bone marrow-derived macrophages (unadjusted p < 0.05), thus defining the transcriptome of macrophages associated with atherosclerosis susceptibility. Using more stringent criteria of twofold or greater change and p < 0.01, 116 and 70 transcripts were overexpressed in lesion-prone and lesion-resistant bone marrow-derived macrophages, respectively. Transcription factor binding site analysis identified two promoter elements that were found more often in the genes overexpressed in the large-lesion group, and one promoter element that was found more often in the small-lesion group. The combination of this expression profiling data with the genetic method of quantitative trait locus mapping should give powerful insights into the genes that affect atherosclerosis susceptibility in mice.
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References
Adams JC, Kureishy N, Taylor AL (2001) A role for syndecan-1 in coupling fascin spike formation by thrombospondin-1. J Cell Biol 152: 1169–1182
Agah R, Topol EJ (2002) Genetic testing for coronary heart disease: the approaching frontier. Exp Rev Mol Diagn 2: 448–460
Boring L, Gosling J, Cleary M, Charo IF (1998) Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394: 894–897
Dansky HM, Barlow CB, Lominska C, Sikes JL, Kao C, et al. (2001). 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
Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, et al. (1998) Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 2: 275–281
Halees AS, Leyfer D, Weng Z (2003) PromoSer: A large-scale mammalian promoter and transcription start site identification service. Nucleic Acids Res 31: 3554–3559
Hosack DA, Dennis G Jr, Sherman BT, Lane HC, Lempicki RA (2003). Identifying biological themes within lists of genes with EASE. Genome Biol 4: R70
Huber W, von Heydebreck A, Sultmann H, Poustka A, Vingron M (2002) Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18(Suppl 1): S96–S104
Plump AS, Smith JD, Hayek T, Aalto-Setala K, Walsh A, et al. (1992). Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71: 343–353
Plump AS, Scott CJ, Breslow JL (1994). Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci U S A 91: 9607–9611
Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B (2004) JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res 32: D91–D94
Schadt EE, Monks SA, Drake TA, Lusis AJ, Che N, et al. (2003). Genetics of gene expression surveyed in maize, mouse and man. Nature 422: 297–302
Smith JD (1998) Mouse models of atherosclerosis. Lab Anim Sci 48: 573–579
Smith JD (2003) Quantitative trait locus mapping for atherosclerosis susceptibility. Curr Opin Lipidol 14: 499–503
Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, et al. (1995). Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A 92: 8264–8268
Smith JD, James D, Dansky HM, Wittkowski KM, Moore KJ, et al. (2003) In silico quantitative trait locus map for atherosclerosis susceptibility in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 23: 117–122
Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW (1988) Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 318: 727–732
Thorn CF, Whitehead AS (2002) Differential transcription of the mouse acute phase serum amyloid A genes in response to pro-inflammatory cytokines. Amyloid 9: 229–236
Wang X, Ishimori N, Korstanje R, Rollins J, Paigen B (2005a) Identifying novel genes for atherosclerosis through mouse-human comparative genetics. Am J Hum Genet 77: 1–15
Wang X, Ria M, Kelmenson PM, Eriksson P, Higgins DC, et al. (2005b) Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nat Genet 37: 365–372
Wegner M (1999) From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res 27: 1409–1420
Yang YH, Speed T (2002) Design issues for cDNA microarray experiments. Nat Rev Genet 3: 579–588
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This work was supported by grant P50HL077107 from the National Heart Lung and Blood Institute of the National Institutes of Health.
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Smith, J.D., Peng, DQ., Dansky, H.M. et al. Transcriptome profile of macrophages from atherosclerosis-sensitive and atherosclerosis-resistant mice. Mamm Genome 17, 220–229 (2006). https://doi.org/10.1007/s00335-005-0099-7
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DOI: https://doi.org/10.1007/s00335-005-0099-7