Abstract
BackgroundAtherosclerosis affects aorta, coronary, carotid, and iliac arteries most frequently than any other body vessel. There may be common molecular pathways sustaining this process. Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis.ResultsWe used DNA microarrays and meta-analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression. We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis. Caveolae and JAK/STAT pathways, and S100A9/S100A8 interacting proteins are certainly involved in the development of vascular disease. We found that the system of caveolae is directly connected with genes that respond to hormone receptors, and indirectly with the apoptosis pathway.Cytokines, chemokines and growth factors released in the blood flux were investigated in parallel. High levels of RANTES, IL-1ra, MIP-1alpha, MIP-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-17, PDGF-BB, VEGF and IFN-gamma were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels.ConclusionThe pattern of cytokine and S100A9/S100A8 up-regulation characterizes atherosclerosis as a proinflammatory disorder. Activation of the JAK/STAT pathway is confirmed by the up-regulation of IL-6, STAT1, ISGF3G and IL10RA genes in coronary and carotid plaques. The functional network constructed in our research is an evidence of the central role of STAT protein and the caveolae system to contribute to preserve the plaque. Moreover, Cav-1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype.
Highlights
Atherosclerosis affects aorta, coronary, carotid, and iliac arteries most frequently than any other body vessel
We decided to adopt an approach where experimental gene expression data are integrated by metanalysis and blood protein measurements to analyze a wider range of pathological samples and patients and to obtain a larger picture of gene/protein interactions involved in atherosclerotic process
We produced gene expression profiles from 8 atherosclerotic left anterior descendent (LAD) coronaries presenting at least 75% stenosis at angiography (PT 1–8), and compared with the profile of a pool made of 10 normal LAD coronaries (PT 9–18)
Summary
Atherosclerosis affects aorta, coronary, carotid, and iliac arteries most frequently than any other body vessel. We analyzed released cytokines and growth factors in the arterial blood of atherosclerotic patients presenting 75% coronary stenosis at least These experimental data have been used simultaneously for two aims: a) confirmation of specific gene expression results and b) completion of specific altered pathways identified by gene expression analysis. This work has led us to the identification of pleiotropic and epistatic gene interactions and of pathways that appear to contribute to preserve the plaque, and to enhance the physiological processes sustaining/attenuating its systemic effects. This information has been useful to define molecular networks underlying the atherosclerotic condition. Our findings may have significance for the development of pharmacological approaches against the central nodes of the identified network, for the prevention or attenuation of atherosclerosis effects on human health
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