A peptide inhibitor of vascular adhesion protein-1 (VAP-1) blocks leukocyte-endothelium interactions under shear stress

Gennady G Yegutkin, Tiina Salminen, Kaisa Koskinen, Christian Kurtis, Michael J McPherson, Sirpa Jalkanen, Marko Salmi

Research output: Contribution to journalArticleScientificpeer-review

39 Citations (Scopus)

Abstract

Vascular adhesion protein-1 (VAP-1) is an endothelial adhesion molecule mediating leukocyte interactions with blood vessels during leukocyte extravasation. Molecularly VAP-1 is a cell-surface-expressed ecto-enzyme belonging to the group of semicarbazide-sensitive amine oxidases (SSAO; EC 2.4.6.3), which deaminate primary amines. Here we asked whether peptides displaying a suitable free amine group could be a substrate or inhibitor of SSAO and thus regulate VAP-1-mediated leukocyte adhesion. On the basis of a molecular model of VAP-1, we designed synthetic peptides that fit to the substrate channel of VAP-1. One of these lysine-containing peptides effectively inhibits VAP-1-dependent lymphocyte rolling and firm adhesion to primary endothelial cells under physiologically relevant shear conditions. The same peptide inhibits the SSAO activity of endothelial and recombinant VAP-1 in a selective and long-lasting manner. We also show that all enzymatically active VAP-1 is displayed on the cell surface. Our results suggest that, in addition to soluble amines, specific cell-surface-bound molecules containing free NH(2) groups in a suitable position may modulate the enzymatic activity of SSAO. Moreover, the inhibitory peptide diminishes leukocyte interactions with endothelial cells under conditions of shear, and thus it may be useful to treat inflammatory conditions.

Original languageEnglish
Pages (from-to)2276-85
Number of pages10
JournalEuropean Journal of Immunology
Volume34
Issue number8
DOIs
Publication statusPublished - Aug 2004
MoE publication typeA1 Journal article-refereed

Keywords

  • Amine Oxidase (Copper-Containing)/antagonists & inhibitors
  • Amino Acids/chemistry
  • Animals
  • Cell Adhesion/physiology
  • Cell Adhesion Molecules/antagonists & inhibitors
  • Endothelium/metabolism
  • Leukocytes/metabolism
  • Membrane Proteins/antagonists & inhibitors
  • Models, Molecular
  • Peptides/metabolism
  • Protein Structure, Tertiary
  • Rabbits

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