title: 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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology, AMC Amsterdam, The Netherlands. ptgbot@gmail.com
authors.forename: Pieter T
authors.initials: PT
authors.lastname: Bot
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grundmann
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
authors.forename: Dominique
authors.initials: D
authors.lastname: de Kleijn
authors.forename: Frans
authors.initials: F
authors.lastname: Moll
authors.forename: Onno
authors.initials: O
authors.lastname: de Boer
authors.forename: Allard C
authors.initials: AC
authors.lastname: van der Wal
authors.forename: Alex
authors.initials: A
authors.lastname: van Soest
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: de Vries
authors.forename: Niels
authors.initials: N
authors.lastname: van Royen
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Piek
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
mesh_terms: D000368:Aged; D002454:Cell Differentiation; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry*; D005260:Female; D005355:Fibrosis / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008264:Macrophages / Q000166:cytology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology*; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000473:pathology*; D012097:Repressor Proteins / Q000378:metabolism*; D013927:Thrombosis / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen