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Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage
BACKGROUND: Endothelial hyper-permeability with plasma leakage and thrombocytopenia are predominant features of severe dengue virus infection. It is well established that heparanase, the endothelial glycocalyx degrading enzyme, plays a major role in various diseases with vascular leakage. It is yet...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722520/ https://www.ncbi.nlm.nih.gov/pubmed/34987504 http://dx.doi.org/10.3389/fimmu.2021.759570 |
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author | Buijsers, Baranca Garishah, Fadel Muhammad Riswari, Silvita Fitri van Ast, Rosalie M. Pramudo, Setyo Gundi Tunjungputri, Rahajeng N. Overheul, Gijs J. van Rij, Ronald P. van der Ven, André Alisjahbana, Bachti Gasem, Muhammad Hussein de Mast, Quirijn van der Vlag, Johan |
author_facet | Buijsers, Baranca Garishah, Fadel Muhammad Riswari, Silvita Fitri van Ast, Rosalie M. Pramudo, Setyo Gundi Tunjungputri, Rahajeng N. Overheul, Gijs J. van Rij, Ronald P. van der Ven, André Alisjahbana, Bachti Gasem, Muhammad Hussein de Mast, Quirijn van der Vlag, Johan |
author_sort | Buijsers, Baranca |
collection | PubMed |
description | BACKGROUND: Endothelial hyper-permeability with plasma leakage and thrombocytopenia are predominant features of severe dengue virus infection. It is well established that heparanase, the endothelial glycocalyx degrading enzyme, plays a major role in various diseases with vascular leakage. It is yet to be elucidated whether heparanase activity plays a major role in dengue-associated plasma leakage. Moreover, the major source of heparanase secretion and activation in dengue remains elusive. Since a relatively high amount of heparanase is stored in platelets, we postulate that heparanase released by activated platelets contributes to the increased plasma heparanase activity during dengue virus infection. METHODS: Heparanase activity (plasma and urine), and heparan sulfate and syndecan-1 (plasma levels) were measured in dengue patients with thrombocytopenia in acute phase (n=30), during course of disease (n=10) and in convalescent phase (n=25). Associations with clinical parameters and plasma leakage markers were explored. Platelets from healthy donors were stimulated with dengue non-structural protein-1, DENV2 virus and thrombin to evaluate heparanase release and activity ex vivo. RESULTS: Heparanase activity was elevated in acute dengue and normalized during convalescence. Similarly, glycocalyx components, such as heparan sulfate and syndecan-1, were increased in acute dengue and restored during convalescence. Increased heparanase activity correlated with the endothelial dysfunction markers heparan sulfate and syndecan-1, as well as clinical markers of plasma leakage such as ascites, hematocrit concentration and gall-bladder wall thickening. Notably, platelet number inversely correlated with heparanase activity. Ex vivo incubation of platelets with thrombin and live DENV2 virus, but not dengue virus-2-derived non-structural protein 1 induced heparanase release from platelets. CONCLUSION: Taken together, our findings suggest that the increase of heparanase activity in dengue patients is associated with endothelial glycocalyx degradation and plasma leakage. Furthermore, thrombin or DENV2 activated platelets may be considered as a potential source of heparanase. |
format | Online Article Text |
id | pubmed-8722520 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-87225202022-01-04 Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage Buijsers, Baranca Garishah, Fadel Muhammad Riswari, Silvita Fitri van Ast, Rosalie M. Pramudo, Setyo Gundi Tunjungputri, Rahajeng N. Overheul, Gijs J. van Rij, Ronald P. van der Ven, André Alisjahbana, Bachti Gasem, Muhammad Hussein de Mast, Quirijn van der Vlag, Johan Front Immunol Immunology BACKGROUND: Endothelial hyper-permeability with plasma leakage and thrombocytopenia are predominant features of severe dengue virus infection. It is well established that heparanase, the endothelial glycocalyx degrading enzyme, plays a major role in various diseases with vascular leakage. It is yet to be elucidated whether heparanase activity plays a major role in dengue-associated plasma leakage. Moreover, the major source of heparanase secretion and activation in dengue remains elusive. Since a relatively high amount of heparanase is stored in platelets, we postulate that heparanase released by activated platelets contributes to the increased plasma heparanase activity during dengue virus infection. METHODS: Heparanase activity (plasma and urine), and heparan sulfate and syndecan-1 (plasma levels) were measured in dengue patients with thrombocytopenia in acute phase (n=30), during course of disease (n=10) and in convalescent phase (n=25). Associations with clinical parameters and plasma leakage markers were explored. Platelets from healthy donors were stimulated with dengue non-structural protein-1, DENV2 virus and thrombin to evaluate heparanase release and activity ex vivo. RESULTS: Heparanase activity was elevated in acute dengue and normalized during convalescence. Similarly, glycocalyx components, such as heparan sulfate and syndecan-1, were increased in acute dengue and restored during convalescence. Increased heparanase activity correlated with the endothelial dysfunction markers heparan sulfate and syndecan-1, as well as clinical markers of plasma leakage such as ascites, hematocrit concentration and gall-bladder wall thickening. Notably, platelet number inversely correlated with heparanase activity. Ex vivo incubation of platelets with thrombin and live DENV2 virus, but not dengue virus-2-derived non-structural protein 1 induced heparanase release from platelets. CONCLUSION: Taken together, our findings suggest that the increase of heparanase activity in dengue patients is associated with endothelial glycocalyx degradation and plasma leakage. Furthermore, thrombin or DENV2 activated platelets may be considered as a potential source of heparanase. Frontiers Media S.A. 2021-12-20 /pmc/articles/PMC8722520/ /pubmed/34987504 http://dx.doi.org/10.3389/fimmu.2021.759570 Text en Copyright © 2021 Buijsers, Garishah, Riswari, van Ast, Pramudo, Tunjungputri, Overheul, van Rij, van der Ven, Alisjahbana, Gasem, de Mast and van der Vlag https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Buijsers, Baranca Garishah, Fadel Muhammad Riswari, Silvita Fitri van Ast, Rosalie M. Pramudo, Setyo Gundi Tunjungputri, Rahajeng N. Overheul, Gijs J. van Rij, Ronald P. van der Ven, André Alisjahbana, Bachti Gasem, Muhammad Hussein de Mast, Quirijn van der Vlag, Johan Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage |
title | Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage |
title_full | Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage |
title_fullStr | Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage |
title_full_unstemmed | Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage |
title_short | Increased Plasma Heparanase Activity and Endothelial Glycocalyx Degradation in Dengue Patients Is Associated With Plasma Leakage |
title_sort | increased plasma heparanase activity and endothelial glycocalyx degradation in dengue patients is associated with plasma leakage |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8722520/ https://www.ncbi.nlm.nih.gov/pubmed/34987504 http://dx.doi.org/10.3389/fimmu.2021.759570 |
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