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 Wittebole, Jean-Luc Balligand, 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 Wittebole, Jean-Luc Balligand
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.
Keywords: Angiotensin II; Endothelial dysfunction; Microvascular thrombosis; Nitric oxide; Oxidative stress; SARS-CoV-2.
Conflict of interest statement
Declaration of interests Marc Derive is a co-founder and employee of Inotrem Company, a drug development company that is developing anti-TREM-1 approaches in septic shock and COVID-19. The other authors have disclosed that they do not have any potential conflicts of interest.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
Figures
References
- Xiong X., Chi J., Gao Q. Prevalence and risk factors of thrombotic events on patients with COVID-19: a systematic review and meta-analysis. Thromb J. 2021;19(1):32.
- Malas M.B., Naazie I.N., Elsayed N., Mathlouthi A., Marmor R., Clary B. Thromboembolism risk of COVID-19 is high and associated with a higher risk of mortality: a systematic review and meta-analysis. EClinicalMedicine. 2020;29
- Lemos A.C.B., do Espirito Santo D.A., Salvetti M.C., et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID) Thromb Res. 2020;196:359–366.
- Libby P., Luscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020;41(32):3038–3044.
- Ackermann M., Verleden S.E., Kuehnel M., et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med. 2020;383(2):120–128.
- Damiani E., Carsetti A., Casarotta E., et al. Microvascular alterations in patients with SARS-COV-2 severe pneumonia. Ann Intensiv Care. 2020;10(1):60.
- Favaron E., Ince C., Hilty M.P., et al. Capillary leukocytes, microaggregates, and the response to hypoxemia in the microcirculation of coronavirus disease 2019 patients. Crit Care Med. 2021;49(4):661–670.
- Scorcella C., Damiani E., Domizi R., et al. MicroDAIMON study: microcirculatory daily monitoring in critically ill patients: a prospective observational study. Ann Intensiv Care. 2018;8(1):64.
- Dominic P., Ahmad J., Bhandari R., et al. Decreased availability of nitric oxide and hydrogen sulfide is a hallmark of COVID-19. Redox Biol. 2021;43
- Yamasaki H. Blood nitrate and nitrite modulating nitric oxide bioavailability: potential therapeutic functions in COVID-19. Nitric Oxide. 2020;103:29–30.
- Green S.J. Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency. Microbes Infect. 2020;22(4-5):149–150.
- Deanfield J.E., Halcox J.P., Rabelink T.J. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285–1295.
- Vanhoutte P.M. Endothelium and control of vascular function. State of the art lecture. Hypertension. 1989;13(6 Pt 2):658–667.
- Lan J., Ge J., Yu J., et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature. 2020;581(7807):215–220.
- Mehta P.K., Griendling K.K. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol. 2007;292(1):C82–C97.
- Liu Y., Yang Y., Zhang C., et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364–374.
- Wu Z., Hu R., Zhang C., Ren W., Yu A., Zhou X. Elevation of plasma angiotensin II level is a potential pathogenesis for the critically ill COVID-19 patients. Crit Care. 2020;24(1):290.
- Henry B.M., Benoit S., Lippi G., Benoit J. Letter to the editor - circulating plasma levels of angiotensin ii and aldosterone in patients with coronavirus disease 2019 (COVID-19): a preliminary report. Prog Cardiovasc Dis. 2020;63(5):702–703.
- Rhodes A., Evans L.E., Alhazzani W., et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensiv Care Med. 2017;43(3):304–377.
- Lobysheva I.I., Biller P., Gallez B., Beauloye C., Balligand J.L. Nitrosylated hemoglobin levels in human venous erythrocytes correlate with vascular endothelial function measured by digital reactive hyperemia. PLoS One. 2013;8(10):e76457.
- Balcarek J., Seva Pessoa B., Bryson C., et al. Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition. Hypertension. 2014;63(5):942–950.
- Group R.C., Horby P., Lim W.S., et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693–704.
- Dikalov S., Fink B. ESR techniques for the detection of nitric oxide in vivo and in tissues. Methods Enzymol. 2005;396:597–610.
- Goshua G., Pine A.B., Meizlish M.L., et al. Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study. Lancet Haematol. 2020;7(8):e575–ee82.
- Philippe A., Chocron R., Gendron N., et al. Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality. Angiogenesis. 2021;24(3):505–517.
- Liao J.K. Linking endothelial dysfunction with endothelial cell activation. J Clin Invest. 2013;123(2):540–541.
- Rovas A., Osiaevi I., Buscher K., et al. Microvascular dysfunction in COVID-19: the MYSTIC study. Angiogenesis. 2021;24(1):145–157.
- Ward S.E., Curley G.F., Lavin M., et al. Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID-19): evidence of acute and sustained endothelial cell activation. Br J Haematol. 2021;192(4):714–719.
- Mancini I., Baronciani L., Artoni A., et al. The ADAMTS13-von Willebrand factor axis in COVID-19 patients. J Thromb Haemost. 2021;19(2):513–521.
- Petrilli C.M., Jones S.A., Yang J., et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020;369:m1966.
- Zhou Y., Yang Q., Chi J., et al. Comorbidities and the risk of severe or fatal outcomes associated with coronavirus disease 2019: a systematic review and meta-analysis. Int J Infect Dis. 2020;99:47–56.
- Carr M.E. Diabetes mellitus: a hypercoagulable state. J Diabetes Complicat. 2001;15(1):44–54.
- Lip G.Y., Li-Saw-Hee F.L. Does hypertension confer a hypercoagulable state? J Hypertens. 1998;16(7):913–916.
- Farah C., Michel L.Y.M., Balligand J.L. Nitric oxide signalling in cardiovascular health and disease. Nat Rev Cardiol. 2018;15(5):292–316.
- Tejero J., Shiva S., Gladwin M.T. Sources of vascular nitric oxide and reactive oxygen species and their regulation. Physiol Rev. 2019;99(1):311–379.
- Dei Zotti F., Lobysheva II, Balligand J.L. Nitrosyl-hemoglobin formation in rodent and human venous erythrocytes reflects NO formation from the vasculature in vivo. PLoS One. 2018;13(7)
- Plonka P.M., Chlopicki S., Wisniewska M., Plonka B.K. Kinetics of increased generation of (.)NO in endotoxaemic rats as measured by EPR. Acta Biochim Pol. 2003;50(3):807–813.
- Westenberger U., Thanner S., Ruf H.H., Gersonde K., Sutter G., Trentz O. Formation of free radicals and nitric oxide derivative of hemoglobin in rats during shock syndrome. Free Radic Res Commun. 1990;11(1-3):167–178.
- Kelm M. Nitric oxide metabolism and breakdown. Biochim Biophys Acta. 1999;1411(2-3):273–289.
- Raschke R.A., Agarwal S., Rangan P., Heise C.W., Curry S.C. Discriminant accuracy of the SOFA score for determining the probable mortality of patients with COVID-19 pneumonia requiring mechanical ventilation. JAMA. 2021
- Vassiliou A.G., Kotanidou A., Dimopoulou I., Orfanos S.E. Endothelial damage in acute respiratory distress syndrome. Int J Mol Sci. 2020;21(22)
- Boulanger C., Luscher T.F. Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide. J Clin Invest. 1990;85(2):587–590.
- Investigators R.C., Investigators AC-a, Investigators A., Goligher E.C., Bradbury C.A., McVerry B.J., et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021;385(9):777–789.
- Chow C.W., Herrera Abreu M.T., Suzuki T., Downey G.P. Oxidative stress and acute lung injury. Am J Respir Cell Mol Biol. 2003;29(4):427–431.
- Grassin-Delyle S., Roquencourt C., Moine P., et al. Metabolomics of exhaled breath in critically ill COVID-19 patients: a pilot study. EBioMedicine. 2021;63
- Yaghoubi N., Youssefi M., Jabbari Azad F., Farzad F., Yavari Z., Zahedi Avval F. Total antioxidant capacity as a marker of severity of COVID-19 infection: possible prognostic and therapeutic clinical application. J Med Virol. 2021
- Biswal S., Remick D.G. Sepsis: redox mechanisms and therapeutic opportunities. Antioxid Redox Signal. 2007;9(11):1959–1961.
- Ware L.B., Fessel J.P., May A.K., Roberts L.J. Plasma biomarkers of oxidant stress and development of organ failure in severe sepsis. Shock. 2011;36(1):12–17.
- Baruah S., Murthy S., Keck K., et al. TREM-1 regulates neutrophil chemotaxis by promoting NOX-dependent superoxide production. J Leukoc Biol. 2019;105(6):1195–1207.
- Cavalcante-Silva L.H.A., Carvalho D.C.M., Lima E.A., et al. Neutrophils and COVID-19: the road so far. Int Immunopharmacol. 2021;90
- Ozkan S., Cakmak F., Konukoglu D., et al. Efficacy of serum angiotensin II levels in prognosis of patients with coronavirus disease 2019. Crit Care Med. 2021;49(6):e613–ee23.
- Lambert D.W., Yarski M., Warner F.J., et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2) J Biol Chem. 2005;280(34):30113–30119.
- Haga S., Yamamoto N., Nakai-Murakami C., et al. Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry. Proc Natl Acad Sci U S A. 2008;105(22):7809–7814.
- Correa T.D., Takala J., Jakob S.M. Angiotensin II in septic shock. Crit Care. 2015;19:98.
- Lawrence A.C., Evin G., Kladis A., Campbell D.J. An alternative strategy for the radioimmunoassay of angiotensin peptides using amino-terminal-directed antisera: measurement of eight angiotensin peptides in human plasma. J Hypertens. 1990;8(8):715–724.
- Zhu Z., Cai T., Fan L., et al. The potential role of serum angiotensin-converting enzyme in coronavirus disease 2019. BMC Infect Dis. 2020;20(1):883.
- Orfanos S.E., Armaganidis A., Glynos C., et al. Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury. Circulation. 2000;102(16):2011–2018.
- Orfanos S.E., Langleben D., Khoury J., et al. Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in humans. Circulation. 1999;99(12):1593–1599.
- Patel V.B., Clarke N., Wang Z., et al. Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS. J Mol Cell Cardiol. 2014;66:167–176.
- Loomis E.D., Sullivan J.C., DA O., Pollock D.M., Pollock J.S. Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther. 2005;315(3):1058–1064.
- To E.E., Vlahos R., Luong R., et al. Endosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy. Nat Commun. 2017;8(1):69.
- Dias S.S.G., Soares V.C., Ferreira A.C., et al. Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators. PLoS Pathog. 2020;16(12)
Source: PubMed