Oxidative stress-induced endothelial dysfunction and decreased vascular nitric oxide in COVID-19 patients

Virginie Montiel*, Irina Lobysheva, Ludovic Gérard, Marjorie Vermeersch, David Perez-Morga, Thomas Castelein, Jean Baptiste Mesland, Philippe Hantson, Christine Collienne, Damien Gruson, Marie Astrid van Dievoet, Alexandre Persu, Christophe Beauloye, Mélanie Dechamps, Leïla Belkhir, Annie Robert, Marc Derive, Pierre François Laterre, A. H.J. Danser, Xavier WitteboleJean Luc Balligand

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: SARS-CoV-2 targets endothelial cells through the angiotensin-converting enzyme 2 receptor. The resulting endothelial injury induces widespread thrombosis and microangiopathy. Nevertheless, early specific markers of endothelial dysfunction and vascular redox status in COVID-19 patients are currently missing. Methods: Observational study including ICU and non-ICU adult COVID-19 patients admitted in hospital for acute respiratory failure, compared with control subjects matched for cardiovascular risk factors similar to ICU COVID-19 patients, and ICU septic shock patients unrelated to COVID-19. Findings: Early SARS-CoV-2 infection was associated with an imbalance between an exacerbated oxidative stress (plasma peroxides levels in ICU patients vs. controls: 1456.0 ± 400.2 vs 436 ± 272.1 mmol/L; P < 0.05) and a reduced nitric oxide bioavailability proportional to disease severity (5-α-nitrosyl-hemoglobin, HbNO in ICU patients vs. controls: 116.1 ± 62.1 vs. 163.3 ± 46.7 nmol/L; P < 0.05). HbNO levels correlated with oxygenation parameters (PaO2/FiO2 ratio) in COVID-19 patients (R2 = 0.13; P < 0.05). Plasma levels of angiotensin II, aldosterone, renin or serum level of TREM-1 ruled out any hyper-activation of the renin-angiotensin-aldosterone system or leucocyte respiratory burst in ICU COVID-19 patients, contrary to septic patients. Interpretation: Endothelial oxidative stress with ensuing decreased NO bioavailability appears as a likely pathogenic factor of endothelial dysfunction in ICU COVID-19 patients. A correlation between NO bioavailability and oxygenation parameters is observed in hospitalized COVID-19 patients. These results highlight an urgent need for oriented research leading to a better understanding of the specific endothelial oxidative stress that occurs during SARS-CoV-2. Funding: Stated in the acknowledgments section.

Original languageEnglish
Article number103893
JournalEBioMedicine
Volume77
DOIs
Publication statusPublished - Mar 2022

Bibliographical note

Funding Information:
We thank Lauriane Michel for helping in organizing the figures. We thank Drs. Lucie Pothen, Halil Yildiz and Jean-Cyr Yombi for their advice and support for the inclusion of severe patients and Dr Diego Castanares y Zapatero for his support for the inclusion of ICU patients. We thank Drs Charles Denis, Adil Wiart, Paul Paccaud, Romain Niessen, and also Julien De Poortere and Julie Bodart for their help to perform blood sample measurements, particularly Lucie Jolly for her participation in TREM-1 dosage and Joël Cosse, Delphine De Mulder, Roxane Verdoy and Delphine Hoton for samples preparation. We thank all the nurses of the ICU and Internal Medicine Unit at the Clinique Universitaires Saint-Luc for their help during technical procedures. We thank Dr Catherine Lambert for her advice and reading of the manuscript. This work was supported by the grants number H.C.046.20F (CUR) from the Fonds National de Recherche Scientifique (FNRS). The CMMI is supported by the European Regional Development Fund and the Walloon Region. VM is a “Specialiste Post-doctorant” of the FNRS; MD is “Specialist Doctorant” of the FNRS; JLB is Senior Investigator of the WELBIO Institute. All data analyzed during this study are included in this published article. Datasets are freely available to reader in the secure online repository Mendeley Data (https://data.mendeley.com//datasets/10.17632/4vsf5hgy6x.5).

Funding Information:
This work was supported by the grants number H.C.046.20F (CUR) from the Fonds National de Recherche Scientifique (FNRS). The CMMI is supported by the European Regional Development Fund and the Walloon Region. VM is a “Specialiste Post-doctorant” of the FNRS; MD is “Specialist Doctorant” of the FNRS; JLB is Senior Investigator of the WELBIO Institute.

Publisher Copyright:
© 2022 The Author(s)

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