Genes Involved in Systemic and Arterial Bed Dependent Atherosclerosis - Tampere Vascular Study

BACKGROUND: Atherosclerosis 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 FINDINGS: We 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). CONCLUSIONS: This 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

The most generally down-regulated genes in atherosclerotic plaques analysed with TaqMan Low Density array.

<p>The results are shown as an average fold change (FC) compared to control arteries.</p

Immunohistochemical staining of lactoferrin (LTF) in advanced human atherosclerotic femoral artery.

<p>The picture was taken with 100× magnitude.</p

Immunohistochemical staining of lactoferrin (LTF) in advanced human atherosclerotic aorta.

<p>The picture was taken with 100× magnitude.</p

The expression of nkTPathway (natural killer T-cell) genes in atherosclerotic plaques from carotid arteries, aortas and femoral arteries compared to non-atherosclerotic internal thoracic arteries analyzed with TaqMan low density array.

<p>Fold changes (FC) are calculated by comparing the median expression of genes in atherosclerotic arteries vs. controls. Notes.</p>*<p>Highly expressed in atherosclerotic plaque.</p

Co-localization of lactoferrin (LTF) with neutrophils and T and B lymphocytes.

<p>Adjacent mirror image sections demonstration the co-localization of LTF (A, C, E) with T-cell marker CD3 (B), neutrophil granulocyte marker elastase (D) and B-cell marker CD20 (F) in aortic plaques. Arrows point cells that are both LTF and CD3-IR (A, B) or LTF and Elastane-IR (C, D). Most of the CD20-IR cells in a lymph nodule (Ln) are also LTF-IR. Large number of LTF-IR cells in surrounding tissue are not CD20-IR. The pictures were taken with 200× magnitude.</p

Genes that were induced only in aortic or femoral plaques compared to non-atherosclerotic internal thoracic arteries analyzed with genome-wide expression array (GWEA).

<p>For all genes, the p-value was less than 0.05.</p

The most up-regulated genes generally in atherosclerotic plaques analysed with TaqMan Low Density array.

<p>The results are shown as an average fold change (FC) compared to control arteries.</p