Genomic profile of foamy and non-foamy granuloma macrophages from fat-fed ApoE null mice or control mice fed a normal diet

Formation of foam cell macrophages (FCMs), which sequester extracellular
modified lipids, is a key event in atherosclerosis. How lipid loading affects
macrophage phenotype is controversial, with evidence suggesting either proor
anti-inflammatory consequences. To investigate this further, we compared
the transcriptomes of foamy and non-foamy macrophages (NFMs) that
accumulate in the subcutaneous granulomas of fed-fat ApoE null mice and
normal chow fed wild-type mice in vivo. Consistent with previous studies,
LXR/RXR pathway genes were significantly over-represented among the genes
up-regulated in foam cell macrophages. Unexpectedly, the hepatic fibrosis
pathway, associated with platelet derived growth factor and transforming
growth factor-β action, was also over-represented. Several collagen
polypeptides and proteoglycan core proteins as well as connective tissue
growth factor and fibrosis-related FOS and JUN transcription factors were upregulated
in foam cell macrophages. Increased expression of several of these
genes was confirmed at the protein level in foam cell macrophages from
subcutaneous granulomas and in atherosclerotic plaques. Moreover,
phosphorylation and nuclear translocation of SMAD2, which is downstream of
several transforming growth factor-β family members, was also detected in
foam cell macrophages. We conclude that foam cell formation in vivo leads to a
pro-fibrotic macrophage phenotype, which could contribute to plaque stability,
especially in early lesions that have few vascular smooth muscle cells.