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

Bot, P.T.; Grundmann, S.; Goumans, M.J.; Kleijn, D. de; Moll, F.; Boer, O. de; ... ; Hoefer, I.E. (2011)

Article / Letter to editor

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 TGF beta signaling. In vitro stimulation of SMCs with TGF beta 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 TGF beta signaling. FoxP1 expression in vitro is induced by TGF beta, resulting in increased collagen and EGR-1 expression, providing a mechanism for the observed association with a more stable plaque phenotype. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

• Atherosclerosis Plaque stability Macrophages Smooth muscle cells TGF-beta nf-kappa-b transcriptional repressors atherosclerotic plaques intraplaque hemorrhage gene-expression t-cells foxp1 endoglin proliferation superfamily

• All authors: Bot, P.T.; Grundmann, S.; Goumans, M.J.; Kleijn, D. de; Moll, F.; Boer, O. de; Wal, A.C. van der; Soest, A. van; Vries, J.P. de; Royen, N. van; Piek, J.J.; Pasterkamp, G.; Hoefer, I.E.
• Date: 2011-09-30
• Journal: Atherosclerosis
• Volume: 218
• Issue: 1
• Pages: 33 - 43
• DOI: doi:10.1016/j.atherosclerosis.2011.05.017