Abstract
BackgroundAtherosclerosis is a complex disease with hundreds of genes influencing its progression. In addition, the phenotype of the disease varies significantly depending on the arterial bed.Methodology/Principal FindingsWe characterized the genes generally involved in human advanced atherosclerotic (AHA type V–VI) plaques in carotid and femoral arteries as well as aortas from 24 subjects of Tampere Vascular study and compared the results to non-atherosclerotic internal thoracic arteries (n=6) using genome-wide expression array and QRT-PCR. In addition we determined genes that were typical for each arterial plaque studied. To gain a comprehensive insight into the pathologic processes in the plaques we also analyzed pathways and gene sets dysregulated in this disease using gene set enrichment analysis (GSEA). According to the selection criteria used (>3.0 fold change and p-value <0.05), 235 genes were up-regulated and 68 genes down-regulated in the carotid plaques, 242 genes up-regulated and 116 down-regulated in the femoral plaques and 256 genes up-regulated and 49 genes down-regulated in the aortic plaques. Nine genes were found to be specifically induced predominantly in aortic plaques, e.g., lactoferrin, and three genes in femoral plaques, e.g., chondroadherin, whereas no gene was found to be specific for carotid plaques. In pathway analysis, a total of 28 pathways or gene sets were found to be significantly dysregulated in atherosclerotic plaques (false discovery rate [FDR] <0.25).ConclusionsThis study describes comprehensively the gene expression changes that generally prevail in human atherosclerotic plaques. In addition, site specific genes induced only in femoral or aortic plaques were found, reflecting that atherosclerotic process has unique features in different vascular beds.
Highlights
Atherosclerosis is a complex disease characterized by endothelial cell dysfunction, smooth muscle cell proliferation and migration, inflammation, lipid and matrix accumulation and thrombus formation with hundreds of genes influencing its progression
Tampere Vascular Study (TVS) material The atherosclerotic vascular sample series for GWEA consists of atherosclerotic plaques from the following arterial sites: femoral artery (n = 4) carotid artery (n = 9) and abdominal aorta (n = 7) and control samples from internal thoracic arteries (ITA) during coronary artery bypass surgery (n = 6) all together from a total of 26 patients participating in Tampere Vascular Study
Several genes were found to have significantly altered expression in advanced atherosclerotic carotid and femoral artery plaques as well as in the aortas studied with GWEA
Summary
Atherosclerosis is a complex disease characterized by endothelial cell dysfunction, smooth muscle cell proliferation and migration, inflammation, lipid and matrix accumulation and thrombus formation with hundreds of genes influencing its progression. Susceptibility to atherosclerosis is in turn influenced by complex gene-gene and gene-environment interactions making atherosclerosis a challenging research subject Gene expression techniques, such as microarrays and representational difference analysis, are powerful tools that can be used to discover the complexities underlying the development of atherosclerotic plaque. This method has previously been used to detect differentially expressed genes in normal and diseased arteries [1,2], disease progression [3], detecting differentially expressed genes according to patient symptomatology [4] and discovering pathways affected in coronary atherosclerosis [5]. The phenotype of the disease varies significantly depending on the arterial bed
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