AUTHOR=Drost Carolin Christina , Rovas Alexandros , Osiaevi Irina , Rauen Matthias , van der Vlag Johan , Buijsers Baranca , Salmenov Rustem , Lukasz Alexander , Pavenstädt Hermann , Linke Wolfgang A. , Kümpers Philipp TITLE=Heparanase Is a Putative Mediator of Endothelial Glycocalyx Damage in COVID-19 – A Proof-of-Concept Study JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.916512 DOI=10.3389/fimmu.2022.916512 ISSN=1664-3224 ABSTRACT=

Coronavirus disease 2019 (COVID-19) is a systemic disease associated with injury (thinning) of the endothelial glycocalyx (eGC), a protective layer on the vascular endothelium. The aim of this translational study was to investigate the role of the eGC-degrading enzyme heparanase (HPSE), which is known to play a central role in the destruction of the eGC in bacterial sepsis. Excess activity of HPSE in plasma from COVID-19 patients correlated with several markers of eGC damage and perfused boundary region (PBR, an inverse estimate of glycocalyx dimensions of vessels with a diameter 4-25 µm). In a series of translational experiments, we demonstrate that the changes in eGC thickness of cultured cells exposed to COVID-19 serum correlated closely with HPSE activity in concordant plasma samples (R = 0.82, P = 0.003). Inhibition of HPSE by a nonanticoagulant heparin fragment prevented eGC injury in response to COVID-19 serum, as shown by atomic force microscopy and immunofluorescence imaging. Our results suggest that the protective effect of heparin in COVID-19 may be due to an eGC-protective off-target effect.