TITLE

BAS/BSCR8 Does macrophage foam cell formation promote extracellular matrix formation or degradation? A genomic study

AUTHOR(S)
Thomas, A. C.; Johnson, J. L.; Eijgelaar, W. J.; Daemen, M. J. A. P.; Newby, A. C.
PUB. DATE
September 2010
SOURCE
Heart;Sep2010, Vol. 96 Issue 17, pe14
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Foam cell macrophage (FCM) formation is an early event in atherosclerosis that precedes both fibrous cap development and subsequent cap rupture; FCM have been implicated in both events. To understand this further we compared the transcriptomes of FCM and non-foamy macrophages (NFM) produced in subcutaneous sponges implanted into fat-fed ApoE null or C57Bl6 mice, respectively (n=4 each). RNA samples of high quality by A260/280>2 were compared on Illumina bead chips. Differential expression was classified as significant (p<0.05 after Bonferroni correction for multiple testing) or suggestive (p<0.001 unadjusted). 62 genes were significantly upregulated and 59 downregulated in FCM compared with NFM. A total of 370 and 381 genes were upregulated and downregulated using the more relaxed criterion. Fold changes confirmed by quantitative RT-PCR (n=5-7) included upregulation of cathepsin C (15í), cathepsin E (19í), matrix metalloproteinase (MMP)-2 (18í) and MMP-23 (22í) but also upregulation of tissue inhibitor of matrix metalloproteinase (TIMP)-2 (4í) and TIMP-3 (8í) and downregulation of MMP-13 (5í). Surprisingly, several matrix proteins were significantly upregulated, including collagen Iα1 (55í) and VIα1 (31í), osteonectin (72í) and biglycan (19í), although thrombospondin declined (2í). Hence our genomic analysis demonstrated changes that could lead to both matrix degradation and deposition. Ingenuity pathway analysis implicated activation of LXR/RXR in FCM, in agreement with other literature, and highlighted responses to platelet-derived growth factor and transforming growth factor β. The hypothesis that interaction of these pathways accounts for the ambiguous behaviour of FCM in matrix remodelling deserves further investigation.
ACCESSION #
55416221

 

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