Factor Xa stimulates Nitric Oxide (NO) release via the effector cell protease receptor-1

Andreas Papapetropoulos, D. C. Altieri, W. C. Sessa

Research output: Contribution to journalArticle

Abstract

Factor Xa (FXa) is a serine protease integral to the clotting cascade that has also been implicated in immune and inflammatory responses. Effector cell protease receptor-1 (EPR-1), a receptor for FXa, is present on vascular endothelial (EC) and smooth muscle cells mediating Ca2+ mobilization, cytokine and growth factor production and cell proliferation in vitro. Exposure of human umbilical vein EC to catalytically active FXa increased cGMP levels, a surrogate marker for NO production, in a dose-dependent manner. cGMP accumulation was abrogated by NO synthase inhibitors. NO production was dependent on the protease activity of factor Xa, as inactive factor Xa and the tick anticoagulant peptide, an active site inhibitor of FXa, blocked NO release. The zymogen, FX and a homologous protease, factor IXa failed to mimic the Xa response. The ability of FXa to stimulate NO production was independent of thrombin generation, since hirudin at a concentration that blocked thrombin stimulated NO production, did not affect FXa responses. In addition, two different agents that inhibit FXa binding to EPR-1 namely a)the peptide LFTRKL and b)the anti-EPR-1 monoclonal antibody (13E5) both attenuated FXa-induced NO release to a degree that correlates with inhibition of FXa binding to EPR-1. A scrambled peptide and a non-binding antibody had no effect on NO release. We conclude that FXa-induced NO production requires binding to EPR-1 and that the NO/cGMP signaling pathway may act as a mediator of the biologic actions of FXa in the vessel wall.

Original languageEnglish (US)
JournalFASEB Journal
Volume12
Issue number5
StatePublished - Mar 20 1998
Externally publishedYes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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