Foam cell formation in vivo is pro-fibrotic

Andrew Newby, Anita Thomas

Research output: Chapter in Book/Report/Conference proceedingConference Contribution (Conference Proceeding)

Abstract

Foam cell formation is a key step in the initiation of atherosclerosis but its role in lesion progression is unclear. To investigate this further, we compared the transcriptomes between mouse foam cell macrophages
(FCMs) generated in subcutaneous sponges in ApoE null mice and nonfoamy macrophages (NFMs) from control C57Bl6 mice using the Illumina platform, validated and extended by quantitative RT-PCR and coupled with immunohistochemistry for proteins and signalling molecules in brachiocephalic artery plaques in ApoE null mice.
From 749 differentially expressed transcripts, Gene Ontology analysis identified the LXR pathway as the most overrepresented; and up-regulation of LXRa,b and RXRa,b and downstream genes was confirmed by qRTPCR. Moreover, we demonstrated increased nuclear LXR translocation in FCMs from sponges or atherosclerotic plaques, consistent with recent data by (Spann NJ, Cell. 2012;151:138-52). However, we found no change markers for macrophage M1/M2 polarization, implying that foam cell formation in itself is neither pro- nor anti-inflammatory.
The second most over-represented pathway was Fibrosis. Most notably, the pro-collagen peptidase, BMP1, and several collagen polypeptide and proteoglycan genes were increased in FCMs, as were connective tissue growth factor andpro-fibrotic signalling molecules of the Fos and Junfamilies. All the
changes were confirmed by qRT-PCR. Moreover, we showed increased production of matrix proteins, CTGF, and phosphorylation of SMAD2, a major transcription factor mediating fibrosis, in FCMs from sponges and plaques.
Our results indicate, somewhat paradoxically, that foam cell formation in vivo is pro-fibrotic, implying that it helps to stabilize plaques.
Original languageEnglish
Title of host publicationAtherosclerosis
Pagese81-e82
Number of pages2
Volume241
Publication statusPublished - 2015

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