Forkhead box protein P1 as a downstream target of transforming growth factor-β induces collagen synthesis and correlates with a more stable plaque phenotype

Abstract Objective Atherosclerosis is an inflammatory disease, modulated by plaque stabilizing and de-stabilizing cell populations such as infiltrating monocytes and vascular smooth muscle cells (vSMCs). Transcription factors regulating proliferation and differentiation of atherosclerosis relevant c...

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Published in:	Atherosclerosis Vol. 218; no. 1; pp. 33 - 43
Main Authors:	Bot, Pieter T, Grundmann, Sebastian, Goumans, Marie-José, de Kleijn, Dominique, Moll, Frans, de Boer, Onno, van der Wal, Allard C, van Soest, Alex, de Vries, Jean-Paul, van Royen, Niels, Piek, Jan J, Pasterkamp, Gerard, Hoefer, Imo E
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ireland Ltd 01-09-2011 Elsevier
Subjects:	Aged Atherosclerosis Atherosclerosis (general aspects, experimental research) Biological and medical sciences Blood and lymphatic vessels Blood vessels and receptors Cardiology. Vascular system Cardiovascular Cell Differentiation Cell Proliferation collagen Collagen - chemistry endothelial cells Female Fibrosis - pathology Forkhead Transcription Factors - metabolism Fundamental and applied biological sciences. Psychology HEK293 Cells Humans immunohistochemistry Immunohistochemistry - methods Macrophages Macrophages - cytology Male Medical sciences Middle Aged monocytes Monocytes - cytology myocytes Phenotype Plaque stability Plaque, Atherosclerotic - pathology Repressor Proteins - metabolism smooth muscle Smooth muscle cells T-lymphocytes TGF-β Thrombosis - pathology transcription factors transforming growth factor beta Transforming Growth Factor beta - metabolism Vertebrates: cardiovascular system Western blotting TGF-β Plaque stability Macrophages Smooth muscle cells Atherosclerosis Transforming growth factor β Glycoprotein Smooth muscle Cardiovascular disease Vascular disease Phenotype Collagen Macrophage
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Summary:	Abstract Objective Atherosclerosis is an inflammatory disease, modulated by plaque stabilizing and de-stabilizing cell populations such as infiltrating monocytes and vascular smooth muscle cells (vSMCs). Transcription factors regulating proliferation and differentiation of atherosclerosis relevant cell types are of interest in this context. The forkhead box transcription factor FoxP1 modulates monocyte differentiation. We studied FoxP1 expression in atherosclerotic tissue, correlated FoxP1 expression with plaque characteristics and identified associations between FoxP1 and plaque proteins. Methods 116 Atherosclerotic plaques from carotid endarterectomy samples were histologically classified (fibrous, fibroatheromatous, atheromatous) and subjected to semi-quantitative protein analysis. Macrophage, SMC content and intraplaque thrombus amount were determined histologically. FoxP1 expression was investigated by western blotting and immunohistochemistry. In addition FoxP1 was overexpressed in vitro to identify causal relations between FoxP1 and plaque proteins. Results FoxP1 expression was observed in SMCs, macrophages, endothelial cells and T-cells within the plaque. High SMC and collagen content correlated with increased FoxP1 isoform (72 kD and 95 kD) levels. 72 kD FoxP1 expression was lower in plaques containing intraplaque thrombus. FoxP1 correlated with active intraplaque TGFβ signaling. In vitro stimulation of SMCs with TGFβ resulted in increased FoxP1 levels. 72 kD FoxP1 correlated with expression of pro-fibrotic EGR-1 and increased Col1A1 expression. Conclusion FoxP1 is expressed by different cell types in atherosclerotic lesions and associated with more stable plaque characteristics and intraplaque TGFβ signaling. FoxP1 expression in vitro is induced by TGFβ, resulting in increased collagen and EGR-1 expression, providing a mechanism for the observed association with a more stable plaque phenotype.
Bibliography:	http://dx.doi.org/10.1016/j.atherosclerosis.2011.05.017 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9150 1879-1484
DOI:	10.1016/j.atherosclerosis.2011.05.017