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 Matthew Black, Thomas P. Kennedy, Alexander Dmitriyevich Verin, Evgeny Alexandrovich Zemskov

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 - Jan 1 2014

Fingerprint

Thrombin
Anticoagulants
Heparin
Permeability
Endothelial Cells
Electric Impedance
Thrombin Receptors
Lung
Myosin Light Chains
Cytoskeletal Proteins
Acute Lung Injury
Adult Respiratory Distress Syndrome
O-desulfated heparin
Fibrin
Thrombocytopenia
Small Interfering RNA
Actins
Pneumonia
Anti-Inflammatory Agents
Phosphorylation

Keywords

  • Endothelium
  • Heparin
  • ODSH
  • PAR
  • Thrombin

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

Cite this

Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner. / Gonzales, Joyce N; Kim, Kyung mi; Zemskova, Marina A.; Rafikov, Ruslan; Heeke, Brenten; Varn, Matthew N.; Black, Stephen Matthew; Kennedy, Thomas P.; Verin, Alexander Dmitriyevich; Zemskov, Evgeny Alexandrovich.

In: Vascular Pharmacology, Vol. 62, No. 2, 01.01.2014, p. 63-71.

Research output: Contribution to journalArticle

Gonzales, JN, Kim, KM, Zemskova, MA, Rafikov, R, Heeke, B, Varn, MN, Black, SM, Kennedy, TP, Verin, AD & Zemskov, EA 2014, 'Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner', Vascular Pharmacology, vol. 62, no. 2, pp. 63-71. https://doi.org/10.1016/j.vph.2014.01.005
Gonzales, Joyce N ; Kim, Kyung mi ; Zemskova, Marina A. ; Rafikov, Ruslan ; Heeke, Brenten ; Varn, Matthew N. ; Black, Stephen Matthew ; Kennedy, Thomas P. ; Verin, Alexander Dmitriyevich ; Zemskov, Evgeny Alexandrovich. / Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner. In: Vascular Pharmacology. 2014 ; Vol. 62, No. 2. pp. 63-71.
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