Modification of the cytoprotective protein C pathway during Dengue virus infection of human endothelial vascular cells

Carlos Cabello-Gutiérrez; Maria Eugenia Manjarrez-Zavala; Alejandra Huerta-Zepeda; Jorge Cime-Castillo; Verónica Monroy-Martínez; Benjamín Biruete-Correa; Blanca H. Ruiz-Ordaz

doi:10.1160/TH08-04-0271

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 101(05): 916-928
DOI: 10.1160/TH08-04-0271

Wound Healing and Inflammation/Infection

Schattauer GmbH

Modification of the cytoprotective protein C pathway during Dengue virus infection of human endothelial vascular cells

Carlos Cabello-Gutiérrez

¹Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF, México

,

Maria Eugenia Manjarrez-Zavala

²Departamento de Virología, Instituto Nacional de Enfermedades Respiratorias, México, DF, México

,

Alejandra Huerta-Zepeda

¹Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF, México

,

Jorge Cime-Castillo

¹Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF, México

,

Verónica Monroy-Martínez

¹Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF, México

,

Benjamín Biruete-Correa

³División de Obstetricia UMAE, Hospital de Ginecología y Obstetricia del IMSS “Luís Castelazo Ayala”, México, DF, México

,

Blanca H. Ruiz-Ordaz

¹Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF, México

› Author Affiliations

Abstract

Summary

Dengue fever (DF) is the most prevalent arthropod-borne viral disease of humans. No safe vaccine is available, there is no experimental animal model and no specific treatment (antiviral) for Dengue virus (DV) infection exists. The pathogenic mechanisms of the severe forms of the disease, such as Dengue shock syndrome (DSS) and Dengue haemorrhagic fever (DHF), in which endothelial damage is the pathognomonic sign, are not fully understood. Clinical observations have revealed significant abnormalities in the coagulation and inflammation systems, with increased levels of soluble thrombomodulin (sTM) in the plasma of patients with DHF/DSS (grade III or IV). Blood sTM was proposed as an early predictor of DSS during the febrile stage. However, the role of the DV in endothelial injury during DSS is unclear. Here, we present novel insights into the participation of DV in the downregulation of the thrombomodulin-thrombin-protein C complex formation at the endothelial surface, with a reduction in activated protein C (APC). APC is the most important vasoprotective protein because it downregulates thrombin generation (by the inactivation of procoagulant factors Va and VIIIa) and has anti-inflammatory, antiapoptotic, and barrier protection properties. These biological functions of APC are associated with the endothelial protein C receptor (EPCR) and pro-tease-activated receptor 1 (PAR-1) signalling pathways, which link the coagulation-inflammation responses. We found alterations in the antithrombotic and cytoprotective protein C pathways during DV infection of human endothelial vascular cells, which may explain the vasculopathy observed during DHF/DSS. Clarification of the basic principles that underlie these processes has important implications for the design of new therapeutic strategies for DHF/DSS.

Keywords

Dengue virus - endothelial cells - APC - thrombomodulin - PAR-1 - EPCR inflammation - coagulation - cytoprotection

Full Text

References

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