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


RESULTS
We 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-1 alpha, MIP-1 beta, 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.


CONCLUSIONS
The 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.
Cagnin
Stefano
S
CRIBI Biotechnology Centre, University of Padova, Padova, Italy. stefanoc@cribi.unipd.it
Biscuola
Michele
M
Patuzzo
Cristina
C
Trabetti
Elisabetta
E
Pasquali
Alessandra
A
Laveder
Paolo
P
Faggian
Giuseppe
G
Iafrancesco
Mauro
M
Mazzucco
Alessandro
A
Pignatti
Pier Franco
PF
Lanfranchi
Gerolamo
G
D000328:Adult; D000368:Aged; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism*; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism*; D021941:Caveolae / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D050791:STAT Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D040501:Calgranulin A; D040502:Calgranulin B; D016207:Cytokines; D050791:STAT Transcription Factors