Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner

Joyce N. Gonzales, Kyung mi Kim, Marina A. Zemskova, Ruslan Rafikov, Brenten Heeke, Matthew N. Varn, Stephen Black, Thomas P. Kennedy, Alexander D. Verin, Evgeny A. Zemskov

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Acute lung injury and acute respiratory distress syndrome are accompanied by thrombin activation and fibrin deposition that enhance lung inflammation, activate endothelial cells and disrupt lung paracellular permeability. Heparin possesses anti-inflammatory properties but its clinical use is limited by hemorrhage and heparin induced thrombocytopenia. We studied the effects of heparin and low anticoagulant 2-O, 3-O desulfated heparin (ODSH) on thrombin-induced increases in paracellular permeability of cultured human pulmonary endothelial cells (ECs). Pretreatment with heparin or ODSH blocked thrombin-induced decrease in the EC transendothelial electrical resistance (TER), attenuated thrombin-stimulated paracellular gap formation and actin cytoskeletal rearrangement. Our data demonstrated that heparin and ODSH had inhibitory effects on thrombin-induced RhoA activation and intracellular calcium elevation. Thrombin-stimulated phosphorylation of the cytoskeletal regulatory proteins, myosin light chain and ezrin/radixin/moesin was also reduced. In these effects, low anticoagulant ODSH was more potent than heparin. Heparin or ODSH alone produced decreases in the EC TER that were abolished by siRNA-mediated depletion of the thrombin receptor, PAR-1. We also demonstrated that, in contrast to heparin, ODSH did not possess thrombin-binding activity. Results suggest that heparin and low anticoagulant ODSH can interfere with thrombin-activated signaling.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalVascular Pharmacology
Volume62
Issue number2
DOIs
StatePublished - Aug 2014

Keywords

  • Endothelium
  • Heparin
  • ODSH
  • PAR
  • Thrombin

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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    Gonzales, J. N., Kim, K. M., Zemskova, M. A., Rafikov, R., Heeke, B., Varn, M. N., Black, S., Kennedy, T. P., Verin, A. D., & Zemskov, E. A. (2014). Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner. Vascular Pharmacology, 62(2), 63-71. https://doi.org/10.1016/j.vph.2014.01.005