Microparticle-associated endothelial protein C receptor and the induction of cytoprotective and anti-inflammatory effects
Open Access
- 1 March 2009
- journal article
- Published by Ferrata Storti Foundation (Haematologica) in Haematologica
- Vol. 94 (3), 387-394
- https://doi.org/10.3324/haematol.13547
Abstract
The endothelial protein C receptor plays an important role within the protein C pathway in regulating coagulation and inflammation. Recently, we described that endothelial protein C receptor can be released in vitro in microparticulate form from primary endothelial cells by exogenous activated protein C. Activated protein C bound to this endothelial protein C receptor retains anticoagulant activity and we hypothesize that this microparticulate endothelial protein C receptor-activated protein C complex can also cleave endothelial protease-activated receptor 1 to modulate inflammation and increase cell survival. Our main objective was, therefore, to study the effect that microparticle-associated endothelial protein C receptor-activated protein C has on endothelial function. Mini-arrays were used and probed with cDNA obtained from endothelial cells after treatment with microparticle-associated endothelial protein C receptor-activated protein C and results were confirmed by real time polymerase chain reaction. The functional relevance of changes at gene level were further analyzed by endothelial apoptosis and permeability assays, in the presence and absence of specific blockade of endothelial protein C receptor, protein C and protease-activated receptor 1. Gene profiling of endothelial cells stimulated by 40 nmol/L activated protein C on microparticles showed significant changes in anti-apoptotic and inflammatory pathways. This was accompanied by protease-activated receptor 1-dependent anti-apoptotic and barrier protective effects, the latter of which also involved sphingosine 1-phosphate receptor and vascular endothelial growth factor receptor-2/ kinase insert domain receptor. Protein C blockade reversed these effects showing specificity for activated protein C on microparticles. Furthermore, confocal microscopy and enzyme-linked immunosorbent assay of plasma obtained from septic patients during recombinant activated protein C treatment showed evidence of their presence in vivo. Activated protein C on microparticle-associated endothelial protein C receptor release can induce protease-activated receptor 1-dependent endothelial effects. The mechanisms underlying barrier protection involve sphingosine 1-phosphate receptor and kinase insert domain receptor.Keywords
This publication has 30 references indexed in Scilit:
- Cellular microparticles: what are they bad or good for?Journal of Thrombosis and Haemostasis, 2003
- Transactivation of Vascular Endothelial Growth Factor (VEGF) Receptor Flk-1/KDR Is Involved in Sphingosine 1-Phosphate-stimulated Phosphorylation of Akt and Endothelial Nitric-oxide Synthase (eNOS)Online Journal of Public Health Informatics, 2002
- Efficacy and Safety of Recombinant Human Activated Protein C for Severe SepsisThe New England Journal of Medicine, 2001
- The Interaction between the Endothelial Cell Protein C Receptor and Protein C Is Dictated by the γ-Carboxyglutamic Acid Domain of Protein COnline Journal of Public Health Informatics, 1997
- Identification of functional endothelial protein C receptor in human plasma.JCI Insight, 1997
- Transcellular activation of platelets and endothelial cells by bioactive lipids in platelet microparticles.JCI Insight, 1997
- The Endothelial Cell Protein C ReceptorOnline Journal of Public Health Informatics, 1996
- Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptorJournal of Biological Chemistry, 1994
- Calcium and Phospholipid Binding Properties of Synthetic .gamma.-Carboxyglutamic Acid-Containing Peptides with Sequence Counterparts in Human Protein CBiochemistry, 1994
- Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in SepsisSocial psychiatry. Sozialpsychiatrie. Psychiatrie sociale, 1992