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Thrombospondin-1 up-regulates expression of cell adhesion molecules and promotes monocyte binding to endothelium

Academic Article
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Overview

authors

  • Narizhneva, N. V.
  • Razorenova, O. V.
  • Podrez, E. A.
  • Chen, J. H.
  • Chandrasekharan, U. M.
  • DiCorleto, P. E.
  • Plow, E. F.
  • Topol, Eric
  • Byzova, T. V.

publication date

  • 2005

journal

  • FASEB Journal  Journal

abstract

  • Expression of cell adhesion molecules (CAM) responsible for leukocyte-endothelium interactions plays a crucial role in inflammation and atherogenesis. Up-regulation of vascular CAM-1 (VCAM-1), intracellular CAM-1 (ICAM-1), and E-selectin expression promotes monocyte recruitment to sites of injury and is considered to be a critical step in atherosclerotic plaque development. Factors that trigger this initial response are not well understood. As platelet activation not only promotes thrombosis but also early stages of atherogenesis, we considered the role of thrombospondin-1 (TSP-1), a matricellular protein released in abundance from activated platelets and accumulated in sites of vascular injury, as a regulator of CAM expression. TSP-1 induced expression of VCAM-1 and ICAM-1 on endothelium of various origins, which in turn, resulted in a significant increase of monocyte attachment. This effect could be mimicked by a peptide derived from the C-terminal domain of TSP-1 and known to interact with CD47 on the cell surface. The essential role of CD47 in the cellular responses to TSP-1 was demonstrated further using inhibitory antibodies and knockdown of CD47 with small interfering RNA. Furthermore, we demonstrated that secretion of endogenous TSP-1 and its interaction with CD47 on the cell surface mediates endothelial response to the major proinflammatory agent, tumor necrosis factor alpha (TNF-alpha). Taken together, this study identifies a novel mechanism regulating CAM expression and subsequent monocyte binding to endothelium, which might influence the development of anti-atherosclerosis therapeutic strategies.

subject areas

  • Antigens, CD47
  • Atherosclerosis
  • Cell Adhesion
  • Cell Adhesion Molecules
  • Cells, Cultured
  • E-Selectin
  • Endothelial Cells
  • Gene Expression Regulation
  • Humans
  • Intercellular Adhesion Molecule-1
  • Monocytes
  • NF-kappa B
  • RNA, Small Interfering
  • Recombinant Proteins
  • Thrombospondin 1
  • Tumor Necrosis Factor-alpha
  • Up-Regulation
  • Vascular Cell Adhesion Molecule-1
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Research

keywords

  • TNF-alpha
  • cardiovascular disease
  • integrin-associated protein
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Identity

PubMed Central ID

  • PMC1569946

International Standard Serial Number (ISSN)

  • 0892-6638

Digital Object Identifier (DOI)

  • 10.1096/fj.04-3310fje

PubMed ID

  • 15833768
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Additional Document Info

start page

  • 1158

end page

  • 1160

volume

  • 19

issue

  • 9

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