COVID-19 and Endothelial Dysfunction: Biomarkers and Potential Drug Mechanisms
Since the ﬁ rst report of pneumonia outbreak in Wuhan by the end of 2019, Coronavirus Disease 2019 (COVID-19) has become a global pandemic; causing millions of deaths globally and aﬀ ecting the rest of worldwide population. The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which enters hosts by inhabiting Angiotensin-Converting Enzyme-2 (ACE-2) receptors expressed in the endothelium layer of not only the respiratory tracts, but also various organs in the body. COVID-19 has been reported to trigger multiple cardiovascular manifestations. Since endothelial dysfunction plays an important role in cardiovascular events and the endothelium is heavily involved in COVID-19 pathophysiology, it is important to investigate their associations and previously established drug potencies to improve endothelial functions as possible treatment options for COVID-19. In this review, we summarize endothelial dysfunction biomarkers involved in COVID-19 and drugs that have shown potential endothelial protective properties to better understand the incidence of endothelial dysfunction in COVID-19 and its future treatment. We searched in PubMed, Wiley Online Library, EBSCO, ScienceDirect databases for literatures containing following keywords: “Endothelial dysfunction”, “COVID-19”, and “biomarkers”. Eligible publications were then assessed and studied to comprise our literature review. A total of 96 studies matched our criteria and provided scientiﬁ c evidences for our review. Materials were then compiled into a review summarizing endothelial biomarkers involved in COVID-19 and potentially repurposed drugs targeting endothelium for COVID-19.Various endothelial dysfunction biomarkers were found to be elevated in COVID19 and is found to be related to its severity, such as adhesion molecules, selectins, PAI-1, and von Willebrand Factors. Multiple drugs targeting the endothelium are also potential and some are under investigation for COVID-19.
Galley HF, Webster NR. Physiology of the endothelium. Br J Anaesth [Internet]. 2004;93(1):105–13. Available from: http://dx.doi.org/10.1093/bja/aeh163
Wang M, Hao H, Leeper NJ, Zhu L. Thrombotic Regulation From the Endothelial Cell Perspectives. Arterioscler Thromb Vasc Biol. 2018;38(6):e90–5.
Siddiqi HK, Libby P, Ridker PM. COVID-19 – A vascular disease. 2020;(January).
Perico L, Benigni A, Casiraghi F, Ng LFP, Renia L, Remuzzi G. Immunity, endothelial injury and complement-induced coagulopathy in COVID-19. Nat Rev Nephrol [Internet]. 2020; Available from: http://dx.doi.org/10.1038/s41581-020-00357-4
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: Testing and clinical relevance. Circulation. 2007;115(10):1285–95.
Halcox JPJ. Endothelial Dysfunction. Prim Auton Nerv Syst. 2012;319–24.
McLean RC, Blumenthal RS. Inflammatory markers and the risk of coronary heart disease. Cardiol Rev. 2005;22(6):41–2.
Ridker PM, Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation. 2004;109(25):6–19.
Tong M, Jiang Y, Xia D, Xiong Y, Zheng Q, Chen F, et al. Elevated Expression of Serum Endothelial Cell Adhesion Molecules in COVID-19 Patients. J Infect Dis. 2020;222(6):894–8.
Nagashima S, Mendes MC, Camargo Martins AP, Borges NH, Godoy TM, Miggiolaro AFRDS, et al. Endothelial dysfunction and thrombosis in patients with COVID-19 - Brief report. Arterioscler Thromb Vasc Biol. 2020;(October):2404–7.
Furie B. P-selectin and blood coagulation: It’s not only about inflammation any more. Arterioscler Thromb Vasc Biol. 2005;25(5):877–8.
Ishiwata N, Takio K, Katayama M, Watanabe K, Titani K, Ikeda Y, et al. Alternatively spliced isoform of P-selectin is present in vivo as a soluble molecule. J Biol Chem. 1994;269(38):23708–15.
André P, Hartwell D, Hrachovinová I, Saffaripour S, Wagner DD. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci U S A. 2000;97(25):13835–40.
Schrijver IT, Kemperman H, Roest M, Kesecioglu J, de Lange DW. Soluble P-selectin as a biomarker for infection and survival in patients with a systemic inflammatory response syndrome on the intensive care unit. Biomark Insights. 2017;12.
Katayama M, Handa M, Araki Y, Ambo H, Kawai Y, Watanabe K, et al. Soluble P‐selectin is present in normal circulation and its plasma level is elevated in patients with thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome. Br J Haematol. 1993;84(4):702–10.
Fraser DD, Patterson EK, Slessarev M, Gill SE, Martin C, Daley M, et al. Endothelial Injury and Glycocalyx Degradation in Critically Ill Coronavirus Disease 2019 Patients: Implications for Microvascular Platelet Aggregation. Crit Care Explor. 2020;2(9):e0194.
Shapiro NI, Schuetz P, Yano K, Sorasaki M, Parikh SM, Jones AE, et al. The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Crit Care. 2010;14(5).
Silva M, Videira PA, Sackstein R. E-selectin ligands in the human mononuclear phagocyte system: Implications for infection, inflammation, and immunotherapy. Front Immunol. 2018;8(JAN).
Smadja DM, Mulliken JB, Bischoff J. E-selectin mediates stem cell adhesion and formation of blood vessels in a murine model of infantile hemangioma. Am J Pathol [Internet]. 2012;181(6):2239–47. Available from: http://dx.doi.org/10.1016/j.ajpath.2012.08.030
Cummings CJ, Sessler CN, Beall LD, Fisher BJ, Best AM, Fowler AA. Soluble E-selectin levels in sepsis and critical illness: Correlation with infection and hemodynamic dysfunction. Am J Respir Crit Care Med. 1997;156(2 I):431–7.
Smadja DM, Guerin CL, Chocron R, Yatim N, Boussier J, Gendron N, et al. Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients. Angiogenesis [Internet]. 2020;23(4):611–20. Available from: https://doi.org/10.1007/s10456-020-09730-0
Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost. 2005;3(8):1879–83.
Fay WP, Korthuis RJ. No Sweetie Pie: Newly Uncovered Role for PAI-1 in Inflammatory Responses to Ischemia/Reperfusion. Physiol Behav. 2019;176(3):139–48.
Praetner M, Zuchtriegel G, Holzer M, Uhl B, Schaubächer J, Mittmann L, et al. Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia-Reperfusion. Arterioscler Thromb Vasc Biol. 2018;38(4):829–42.
Vaughan DE, Rai R, Khan SS, Eren M, Ghosh AK. Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence. Arterioscler Thromb Vasc Biol. 2017;37(8):1446–52.
Ji Y, Weng Z, Fish P, Goyal N, Luo M, Myears SP, et al. Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation. Physiol Behav [Internet]. 2017;176(10):139–48. Available from: file:///C:/Users/Carla Carolina/Desktop/Artigos para acrescentar na qualificação/The impact of birth weight on cardiovascular disease risk in the.pdf
Whyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ. Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. J Thromb Haemost. 2020;18(7):1548–55.
Fox SE, Akmatbekov A, Harbert JL, Li G, Brown JQ, Heide RS Vander. Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans. 2020;(January):19–21.
Meltzer ME, Lisman T, De Groot PG, Meijers JCM, Le Cessie S, Doggen CJM, et al. Venous thrombosis risk associated with plasma hypofibrinolysis is explained by elevated plasma levels of TAFI and PAI-1. Blood. 2010;116(1):113–21.
Zuo Y, Warnock M, Harbaugh A, Yalavarthi S, Gockman K, Lawrence DA. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. 2020;1–13.
Varga Z, Flammer A, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endothelitis in COVID-19. Ann Oncol. 2020;(January).
Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. Proc Natl Acad Sci U S A. 2020;117(36):22351–6.
Nougier C, Benoit R, Simon M, Desmurs-Clavel H, Marcotte G, Argaud L, et al. Hypofibrinolytic state and high thrombin generation may play a major role in SARS-COV2 associated thrombosis. J Thromb Haemost. 2020;18(9):2215–9.
Blasi A, von Meijenfeldt FA, Adelmeijer J, Calvo A, Ibañez C, Perdomo J, et al. In vitro hypercoagulability and ongoing in vivo activation of coagulation and fibrinolysis in COVID-19 patients on anticoagulation. J Thromb Haemost. 2020;18(10):2646–53.
Löf A, Müller JP, Brehm MA. A biophysical view on von Willebrand factor activation. J Cell Physiol. 2018;233(2):799–810.
Da Silva ML, Cutler DF. Von Willebrand factor multimerization and the polarity of secretory pathways in endothelial cells. Blood. 2016;128(2):277–85.
Butera D, Passam F, Ju L, Cook KM, Woon H, Aponte-Santamaría C, et al. Autoregulation of von Willebrand factor function by a disulfide bond switch. Sci Adv. 2018;4(2).
Verhenne S, Denorme F, Libbrecht S, Vandenbulcke A, Pareyn I, Deckmyn H, et al. Platelet-derived VWF is not essential for normal thrombosis and hemostasis but fosters ischemic stroke injury in mice. Blood. 2015;126(14):1715–22.
Doddapattar P, Dhanesha N, Chorawala MR, Tinsman C, Jain M, Nayak MK, et al. Endothelial cell-derived von Willebrand factor, but not platelet- derived, promotes atherosclerosis in Apoe-deficient mice. 2019;38(3):319–35.
Kayal S, Jaïs JP, Aguini N, Chaudière J, Labrousse J. Elevated circulating E-selectin, intercellular adhesion molecule 1, and von Willebrand factor in patients with severe infection. Am J Respir Crit Care Med. 1998;157(3 PART I):776–84.
Meyer AA, Kundt G, Steiner M, Schuff-Werner P, Kienast W. Impaired flow-mediated vasodilation, carotid artery intima-media thickening, and elevated endothelial plasma markers in obese children: The impact of cardiovascular risk factors. Pediatrics. 2006;117(5):1560–7.
Mannucci PM. von Willebrand Factor A Marker of Endothelial Damage? Greece Rome. 1967;14(2):188–98.
Grobler C, Maphumulo SC, Grobbelaar LM, Bredenkamp JC, Laubscher GJ, Lourens PJ, et al. Covid-19: The rollercoaster of fibrin(ogen), d-dimer, von willebrand factor, p-selectin and their interactions with endothelial cells, platelets and erythrocytes. Int J Mol Sci. 2020;21(14):1–25.
Iba T, Levy JH, Connors JM, Warkentin TE, Thachil J, Levi M. The unique characteristics of COVID-19 coagulopathy. Crit Care. 2020;24(1):4–11.
Kawecki C, Lenting PJ, Denis C V. von Willebrand factor and inflammation. J Thromb Haemost. 2017;15(7):1285–94.
Breakey N, Escher R. D-dimer and mortality in COVID-19: A self-fulfilling prophecy or a pathophysiological clue? Swiss Med Wkly. 2020;150(21–22):1–7.
Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med [Internet]. 2020;46(6):1089–98. Available from: https://doi.org/10.1007/s00134-020-06062-x
Morici N, Bottiroli M, Fumagalli R, Marini C, Cattaneo M. Role of von Willebrand Factor and ADAMTS-13 in the Pathogenesis of Thrombi in SARS-CoV-2 Infection: Time to Rethink. Thromb Haemost. 2020;120(9):1339–41.
Bazzan M, Montaruli B, Sciascia S, Cosseddu D, Norbiato C, Roccatello D. Low ADAMTS 13 plasma levels are predictors of mortality in COVID-19 patients. Intern Emerg Med [Internet]. 2020;15(5):861–3. Available from: https://doi.org/10.1007/s11739-020-02394-0
Huisman A, Beun R, Sikma M, Westerink J, Kusadasi N. Involvement of ADAMTS13 and von Willebrand factor in thromboembolic events in patients infected with SARS-CoV-2. Int J Lab Hematol. 2020;42(5):e211–2.
Adam E, Zacharowski K, Miesbach W. A comprehensive assessment of the coagulation profile in critically ill COVID-19 patients. 2020;(January).
Latimer G, Corriveau C, DeBiasi RL, Jantausch B, Delaney M, Jacquot C, et al. Cardiac dysfunction and thrombocytopenia-associated multiple organ failure inflammation phenotype in a severe paediatric case of COVID-19. 2020;(January):19–21.
Katneni UK, Alexaki A, Hunt RC, Schiller T, Dicuccio M, Buehler PW, et al. Coagulopathy and thrombosis as a result of severe COVID-19 infection: A microvascular focus. Thromb Haemost. 2020;
Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18(7):1738–42.
Rauch A, Labreuche J, Lassalle F, Goutay J, Caplan M, Charbonnier L, et al. Coagulation biomarkers are independent predictors of increased oxygen requirements in COVID-19. J Thromb Haemost. 2020;(August):1–12.
Sugiyama MG, Gamage A, Zyla R, Armstrong SM, Advani S, Advani A, et al. Influenza Virus Infection Induces Platelet-Endothelial Adhesion Which Contributes to Lung Injury. J Virol. 2016;90(4):1812–23.
Mojiri A, Nakhaii-Nejad M, Phan WL, Kulak S, Radziwon-Balicka A, Jurasz P, et al. Hypoxia results in upregulation and de novo activation of von willebrand factor expression in lung endothelial cells. Arterioscler Thromb Vasc Biol. 2013;33(6):1329–38.
Pinsky DJ, Naka Y, Liao H, Oz MC, Wagner DD, Mayadas TN, et al. Hypoxia-induced exocytosis of endothelial cell weibel-palade bodies: A mechanism for rapid neutrophil recruitment after cardiac preservation. J Clin Invest. 1996;97(2):493–500.
Mojiri A, Alavi P, Lorenzana Carrillo MA, Nakhaei-Nejad M, Sergi CM, Thebaud B, et al. Endothelial cells of different organs exhibit heterogeneity in von Willebrand factor expression in response to hypoxia. Atherosclerosis [Internet]. 2019;282(June 2018):1–10. Available from: https://doi.org/10.1016/j.atherosclerosis.2019.01.002
Matsuura Y, Yamashita A, Iwakiri T, Sugita C, Okuyama N, Kitamura K, et al. Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity. Thromb Haemost. 2015;114(1):158–72.
Ogawa S, Clauss M, Kuwabara K, Shreeniwas R, Butura C, Koga S, et al. Hypoxia induces endothelial cell synthesis of membrane-associated proteins. Proc Natl Acad Sci U S A. 1991;88(21):9897–901.
Fearns C, Loskutoff DJ. Induction of plasminogen activator inhibitor 1 gene expression in murine liver by lipopolysaccharide: Cellular localization and role of endogenous tumor necrosis factor-α. Am J Pathol. 1997;150(2):579–90.
Gragnano F, Sperlongano S, Golia E, Natale F, Bianchi R, Crisci M, et al. The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy. Mediators Inflamm. 2017;2017.
Andersson HM, Siegerink B, Luken BM, Crawley JTB, Algra A, Lane DA, et al. High VWF, low ADAMTS13, and oral contraceptives increase the risk of ischemic stroke and myocardial infarction in young women. Blood. 2012;119(6):1555–60.
Hoechter DJ, Becker-pennrich A, Langrehr J, Bruegel M, Zwissler B, Schaefer S. Higher procoagulatory potential but lower DIC score in COVID-19 ARDS patients compared to non-COVID-19 ARDS patients. 2020;(January).
Varin R, Mulder P, Tamion F, Richard V, Henry JP, Lallemand F, et al. Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure: Role of nitric oxide, prostanoids, oxidant stress, and bradykinin. Circulation. 2000;102(3):351–6.
Mancini GBJ, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease: The TREND (Trial on Reversing ENdothelial Dysfunction) study. Circulation. 1996;94(3):258–65.
Fujii M, Wada A, Tsutamoto T, Ohnishi M, Isono T, Kinoshita M. Bradykinin improves left ventricular diastolic function under long-term angiotensin-converting enzyme inhibition in heart failure. Hypertension. 2002;39(5):952–7.
Bachetti T, Comini L, Pasini E, Cargnoni A, Curello S, Ferrari R. Ace-inhibition with quinapril modulates the nitric oxide pathway in normotensive rats. J Mol Cell Cardiol. 2001;33(3):395–403.
Mukai Y, Shimokawa H, Higashi M, Morikawa K, Matoba T, Hiroki J, et al. Inhibition of renin-angiotensin system ameliorates endothelial dysfunction associated with aging in rats. Arterioscler Thromb Vasc Biol. 2002;22(9):1445–50.
Sola S, Mir MQS, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: Results of the Irbesartan and Lipoic Acid in Endothelial Dysfunction (ISLAND) study. Circulation. 2005;111(3):343–8.
Shahin Y, Khan JA, Samuel N, Chetter I. Angiotensin converting enzyme inhibitors effect on endothelial dysfunction: A meta-analysis of randomised controlled trials. Atherosclerosis [Internet]. 2011;216(1):7–16. Available from: http://dx.doi.org/10.1016/j.atherosclerosis.2011.02.044
Hasan SS, Kow CS, Hadi MA, Zaidi STR, Merchant HA. Mortality and Disease Severity Among COVID-19 Patients Receiving Renin-Angiotensin System Inhibitors: A Systematic Review and Meta-analysis. Am J Cardiovasc Drugs [Internet]. 2020;20(6):571–90. Available from: https://doi.org/10.1007/s40256-020-00439-5
Liu X, Long C, Xiong Q, Chen C, Ma J, Su Y, et al. Association of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with risk of COVID-19, inflammation level, severity, and death in patients with COVID-19: A rapid systematic review and meta-analysis. Clin Cardiol. 2020;
Martínez-gonzález J, Raposo B, Rodríguez C, Badimon L. Downregulation by Atherogenic Levels of Native LDLs Balance Between Transcriptional and Posttranscriptional Regulation. 2001;804–9.
Laufs U, Fata V La, Plutzky J, Liao JK. Upregulation of Endothelial Nitric Oxide Synthase by HMG CoA Reductase Inhibitors Ulrich. 1998;1129–35.
Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid lowering - Are they clinically relevant? Eur Heart J. 2003;24(3):225–48.
Aviram M, Hussein O, Rosenblat M, Schlezinger S, Hayek T, Keidar S. Interactions of platelets, macrophages, and lipoproteins in hypercholesterolemia: Antiatherogenic effects of HMG-CoA reductase inhibitor therapy. J Cardiovasc Pharmacol. 1998;31(1):39–45.
Sánchez-Quesada JL, Otal-Entraigas C, Franco M, Jorba O, González-Sastre F, Blanco-Vaca F, et al. Effect of simvastatin treatment on the electronegative low-density lipoprotein present in patients with heterozygous familial hypercholesterolemia. Am J Cardiol. 1999;84(6):655–9.
Kureishi Y, Luo Z, Shiojima I, Bialik A, Fulton D, David J, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. 2010;6(9):1004–10.
Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The Effect of Cholesterol-Lowering and Antioxidant Therapy on Endothelium-Dependent Coronary Vasomotion. J Occup Environ Med. 1996;38(5):468.
Ascer E, Bertolami MC, Venturinelli ML, Buccheri V, Souza J, Nicolau JC, et al. Atorvastatin reduces proinflammatory markers in hypercholesterolemic patients. Atherosclerosis. 2004;177(1):161–6.
Kirmizis D, Papagianni A, Dogrammatzi F, Skoura L, Belechri AM, Alexopoulos E, et al. Effects of simvastatin on markers of inflammation, oxidative stress and endothelial cell apoptosis in patients on chronic hemodialysis. J Atheroscler Thromb. 2010;17(12):1256–65.
Reriani MK, Dunlay SM, Gupta B, West CP, Rihal CS, Lerman LO, et al. Effects of statins on coronary and peripheral endothelial function in humans: A systematic review and metaanalysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil. 2011;18(5):704–16.
Dimmeler S, Aicher A, Vasa M, Mildner-rihm C, Adler K, Tiemann M, et al. increase endothelial progenitor cells via the PI 3-kinase / Akt pathway. 2001;108(3):365–6.
Tiefenbacher CP, Friedrich S, Bleeke T, Vahl C, Chen X, Niroomand F. ACE inhibitors and statins acutely improve endothelial dysfunction of human coronary arterioles. Am J Physiol - Hear Circ Physiol. 2004;286(4 55-4):1425–32.
Masana L, Correig E, Borjabad CR, Anoro E, Arroyo JA, Al E. EFFECT OF STATIN THERAPY ON SARS-CoV-2 INFECTION-RELATED MORTALITY IN HOSPITALIZED PATIENTS. Akrab Juara [Internet]. 2020;5(1):43–54. Available from: http://www.akrabjuara.com/index.php/akrabjuara/article/view/919
Saeed O, Castagna F, Agalliu I, Xue X, Patel SR, Rochlani Y, et al. Statin Use and In‐Hospital Mortality in Diabetics with COVID‐19. J Am Heart Assoc. 2020;
Song SL, Hays SB, Panton CE, Mylona EK, Kalligeros M, Shehadeh F, et al. Statin use is associated with decreased risk of invasive mechanical ventilation in COVID-19 patients: A preliminary study. Pathogens. 2020;9(9):1–9.
Heitzer T, Just H, Münzel T. Antioxidant Vitamin C Improves Endothelial Dysfunction in Chronic Smokers. Circulation. 1996;94(1):6–9.
Matsumoto T, D’Uscio L V., Eguchi D, Akiyama M, Smith LA, Katusic ZS. Protective effect of chronic vitamin C treatment on endothelial function of apolipoprotein E-deficient mouse carotid artery. J Pharmacol Exp Ther. 2003;306(1):103–8.
Carr AC, McCall MR, Frei B. Oxidation of LDL by myeloperoxidase and reactive nitrogen species: Reaction pathways and antioxidant protection. Arterioscler Thromb Vasc Biol. 2000;20(7):1716–23.
Traber MG, Stevens JF. Vitamins C and E: Beneficial effects from a mechanistic perspective. Free Radic Biol Med. 2011;51(5):1000–13.
Scioli MG, Bielli A, Agostinelli S, Tarquini C, Arcuri G, Ferlosio A, et al. Antioxidant treatment prevents serum deprivation- and TNF-α-induced endothelial dysfunction through the inhibition of NADPH oxidase 4 and the restoration of β-oxidation. J Vasc Res. 2014;51(5):327–37.
Chen J, Reheman A, Gushiken FC, Nolasco L, Fu X, Moake JL, et al. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest. 2011;121(2):593–603.
Shapiro, N.I., Schuetz, P., Yano, K. et al. The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Crit Care 14, R182 (2010). https://doi.org/10.1186/cc9290
The Indonesian Journal of Tropical and Infectious Disease (IJTID) is a scientific peer-reviewed journal freely available to be accessed, downloaded, and used for research. All articles published in the IJTID are licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which is under the following terms:
Attribution — You must give appropriate credit, link to the license, and indicate if changes were made. You may do so reasonably, but not in any way that suggests the licensor endorses you or your use.
NonCommercial — You may not use the material for commercial purposes.
ShareAlike — If you remix, transform, or build upon the material, you must distribute your contributions under the same license as the original.
No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.