Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries

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.

Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

“…Interestingly, analysis of expression profile studies using human genomic microarrays shows significant up-regulation of TRPC3 mRNA levels in plaques derived from patients with atherosclerotic lesions in the left anterior descendent coronary artery (31). In circulating monocytes from three out of four patients homozygous for familial hypercholesterolemia, the TRPC3 mRNA was notoriously up-regulated compared with heterozygous or control patients (32).…”

Macrophage Inflammatory Protein-1β and Fibrinogen Are Synergistic Predictive Markers of Prognosis of Intermediate Coronary Artery Lesions

“…A number of chemoattractant cytokines, such as macrophage inflammatory protein (MIP)-1β, MIP-1α, monocyte chemotactic proteins and regulated upon activation, normal T cell expressed and secreted (RANTES) [3], may participate in signaling the entry of adherent monocytes into the artery wall, where they accumulate lipid and transform into macrophage foam cells. In one study, high levels of MIP-1β were found in plasma of atherosclerotic patients [4]. MIP-1β gene expression has been found to be elevated in Kawasaki disease [5] and heart failure [6,7].…”

Identification of lipid droplet-associated proteins in the formation of macrophage-derived foam cells using microarrays

“…However, the genes reported mainly focus on aspects of regulation of cell apoptosis (8)(9)(10), growth (11), mobility (12), inflammation (13), and signal transduction (14,15), while the mechanisms of lipid droplet (LD) formation were largely ignored or underestimated in these studies. Disorders of lipid homeostasis have been seen as the major factors influencing atherosclerotic traits (16), including cholesterol clearance from foam cells, removal of fatty acids and lipoproteins, and lipid transportation in cell organelles. The most recent studies have proven that LD-associated proteins contribute to the regulation of cellular lipid stores, nascent LD biogenesis and lipid metabolism and transport (17)(18)(19).…”