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Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype.

Thomas AC, Eijgelaar WJ, Daemen MJ, Newby AC - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.

ABSTRACT
Formation of foam cell macrophages, which sequester extracellular modified lipids, is a key event in atherosclerosis. How lipid loading affects macrophage phenotype is controversial, with evidence suggesting either pro- or anti-inflammatory consequences. To investigate this further, we compared the transcriptomes of foamy and non-foamy macrophages that accumulate in the subcutaneous granulomas of fed-fat ApoE 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 up-regulated 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.

No MeSH data available.


Related in: MedlinePlus

CTGF in sponges and arteries from mice.CTGF (red) is present in A) in FCMs, but not B) NFMs isolated from sponges. Blue = nuclei (DAPI). CTGF (brown) is present in C) FCMs in sponge sections or; D) throughout the plaque, media and adventitia of a brachiocephalic artery from a fat-fed ApoE  mouse. E) sponge section negative control; F) negative control in a section from a brachiocephalic artery plaque. Magnification x 200 (C, E), x 400 (A, B, D, F).
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pone.0128163.g006: CTGF in sponges and arteries from mice.CTGF (red) is present in A) in FCMs, but not B) NFMs isolated from sponges. Blue = nuclei (DAPI). CTGF (brown) is present in C) FCMs in sponge sections or; D) throughout the plaque, media and adventitia of a brachiocephalic artery from a fat-fed ApoE mouse. E) sponge section negative control; F) negative control in a section from a brachiocephalic artery plaque. Magnification x 200 (C, E), x 400 (A, B, D, F).

Mentions: Most FCMs but very few NFMs isolated from sponges stained for CTGF (Fig 6A and 6B; red staining), which supports the mRNA data. Of cells in sponge sections from fat-fed ApoE mice, 49 ± 22% (n = 10) stained for CTGF (arrows in Fig 6C). FCMs in brachiocephalic artery plaque sections also had strong staining for CTGF (Fig 6D). SMC in the media also stained for CTGF, as did the extracellular matrix of the adventitia, which obscured any staining by adventitial cells. Approximately 90–95% (n = 6–7) of cells in the plaque, media and adventitia stained for CTGF protein, intracellularly or in the surrounding matrix. This data therefore confirmed the over expression of CTGF in sponge and plaque FCMs, and suggested that there might be reduced staining from NFMs, at least in in the sponges.


Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype.

Thomas AC, Eijgelaar WJ, Daemen MJ, Newby AC - PLoS ONE (2015)

CTGF in sponges and arteries from mice.CTGF (red) is present in A) in FCMs, but not B) NFMs isolated from sponges. Blue = nuclei (DAPI). CTGF (brown) is present in C) FCMs in sponge sections or; D) throughout the plaque, media and adventitia of a brachiocephalic artery from a fat-fed ApoE  mouse. E) sponge section negative control; F) negative control in a section from a brachiocephalic artery plaque. Magnification x 200 (C, E), x 400 (A, B, D, F).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4510387&req=5

pone.0128163.g006: CTGF in sponges and arteries from mice.CTGF (red) is present in A) in FCMs, but not B) NFMs isolated from sponges. Blue = nuclei (DAPI). CTGF (brown) is present in C) FCMs in sponge sections or; D) throughout the plaque, media and adventitia of a brachiocephalic artery from a fat-fed ApoE mouse. E) sponge section negative control; F) negative control in a section from a brachiocephalic artery plaque. Magnification x 200 (C, E), x 400 (A, B, D, F).
Mentions: Most FCMs but very few NFMs isolated from sponges stained for CTGF (Fig 6A and 6B; red staining), which supports the mRNA data. Of cells in sponge sections from fat-fed ApoE mice, 49 ± 22% (n = 10) stained for CTGF (arrows in Fig 6C). FCMs in brachiocephalic artery plaque sections also had strong staining for CTGF (Fig 6D). SMC in the media also stained for CTGF, as did the extracellular matrix of the adventitia, which obscured any staining by adventitial cells. Approximately 90–95% (n = 6–7) of cells in the plaque, media and adventitia stained for CTGF protein, intracellularly or in the surrounding matrix. This data therefore confirmed the over expression of CTGF in sponge and plaque FCMs, and suggested that there might be reduced staining from NFMs, at least in in the sponges.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Bristol Heart Institute, University of Bristol, Bristol, United Kingdom.

ABSTRACT
Formation of foam cell macrophages, which sequester extracellular modified lipids, is a key event in atherosclerosis. How lipid loading affects macrophage phenotype is controversial, with evidence suggesting either pro- or anti-inflammatory consequences. To investigate this further, we compared the transcriptomes of foamy and non-foamy macrophages that accumulate in the subcutaneous granulomas of fed-fat ApoE 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 up-regulated 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.

No MeSH data available.


Related in: MedlinePlus