Angiotensin converting enzyme 2 gene expression and markers of oxidative stress are correlated with disease severity in patients with COVID-19
Afraa S H Alobaidy, Mona Elhelaly, Maggie E Amer, Rasha S Shemies, Azza I Othman, Mohamed A El-Missiry
Molecular Biology Reports, doi:10.1007/s11033-023-08515-0
Background Oxidative stress is thought to play a significant role in the pathogenesis and severity of COVID-19. Additionally, angiotensin converting enzyme 2 (ACE2) expression may predict the severity and clinical course of COVID-19. Accordingly, the aim of the present study was to evaluate the association of oxidative stress and ACE2 expression with the clinical severity in patients with COVID-19.
Methods and results The present study comprised 40 patients with COVID-19 and 40 matched healthy controls, recruited between September 2021 and March 2022. ACE 2 expression levels were measured using Hera plus SYBR Green qPCR kits with GAPDH used as an internal control. Serum melatonin (MLT) levels, serum malondialdehyde (MDA) levels, and total antioxidant capacity (TAC) were estimated using ELISA. The correlations between the levels of the studied markers and clinical indicators of disease severity were evaluated. Significantly, lower expression of ACE2 was observed in COVID-19 patients compared to controls. Patients with COVID-19 had lower serum levels of TAC and MLT but higher serum levels of MDA compared to normal controls. Serum MDA levels were correlated with diastolic blood pressure (DBP), Glasgow coma scale (GCS) scores, and serum potassium levels. Serum MLT levels were positively correlated with DBP, mean arterial pressure (MAP), respiratory rate, and serum potassium levels. TAC was correlated with GCS, mean platelet volume, and serum creatinine levels. Serum MLT levels were significantly lower in patients treated with remdesivir and inotropes. Receiver operating characteristic curve analysis demonstrates that all markers had utility in discriminating COVID-19 patients from healthy controls. Conclusions Increased oxidative stress and increased ACE2 expression were correlated with disease severity and poor outcomes in hospitalized patients with COVID-19 in the present study. Melatonin supplementation may provide a utility as an adjuvant therapy in decreasing disease severity and death in COVID-19 patients.
Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by ASA, MEE, MEA, RSS, AIO, MAEM. The first draft of the manuscript was written and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding Open access funding provided by The Science, Technology & Innovation Funding Authority (STDF) in cooperation with The Egyptian Knowledge Bank (EKB). This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Data availability All data generated or analyzed during this study are included in this published article.
Declarations Conflict of interest The authors declare that they have no conflict of interest to declare.
Ethics approval The study protocol was carried according to Institutional Ethics Committee of Mansoura University, Egypt (approval number sci-Z-ph-2021-60) which performed in compliance with the ethical guidelines outlined in the 1964 Helsinki Declaration. Patients have signed informed consent form.
Consent to participate Not applicable.
Consent to publish Not applicable. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
Biancatelli, Berrill, Mohammed, Marik, Melatonin for the treatment of sepsis: the scientific rationale, J Thorac Dis,
doi:10.21037/jtd.2019.12.85
Chuang, Shiesh, Chi, Tu, Hor et al., Serum total antioxidant capacity reflects severity of illness in patients with severe sepsis, Crit Care,
doi:10.1186/cc4826
Cook, Ausiello, Functional ACE2 deficiency leading to angiotensin imbalance in the pathophysiology of COVID-19, Rev Endocr Metab Disord,
doi:10.1007/s11154-021-09663-z
Cunnane, Manku, Oka, Horrobin, Enhanced vascular reactivity to various vasoconstrictor agents following pinealectomy in the rat: role of melatonin, Can J Physiol Pharmacol,
doi:10.1139/y80-049
Darif, Hammi, Kihel, Idrissi, Guessous et al., The pro-inflammatory cytokines in COVID-19 pathogenesis: what goes wrong?, Microb Pathog,
doi:10.1016/j.micpath.2021.104799
De Las, Giménez, Ferder, Manucha, Lahera, Implications of oxidative stress and potential role of mitochondrial dysfunction in COVID-19: therapeutic effects of vitamin D, Antioxidants,
doi:10.3390/antiox9090897
Delgado-Roche, Mesta, Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection, Arch Med Res,
doi:10.1016/j.arcmed.2020.04.019
El-Missiry, El-Missiry, Othman, Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19, Eur J Pharmacol,
doi:10.1016/j.ejphar.2020.173329
El-Missiry, Othman, Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19, Eur J Pharmacol,
doi:10.1016/j.ejphar.2020.173329
El-Sokkary, Reiter, Cuzzocrea, Caputi, Hassanein et al., Role of melatonin in reduction of lipid peroxidation and peroxynitrite formation in non-septic shock induced by zymosan, Shock,
doi:10.1097/00024382-199911000-00009
Gheblawi, Viveiros, Nguyen, Zhong, Turner et al., Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2, Circ Res,
doi:10.1161/circresaha.120.317015
Giovannini, Chiarla, Giuliante, Pallavicini, Vellone et al., Serum uric acid, creatinine, and the assessment of antioxidant capacity in critical illness, Crit Care,
doi:10.1186/cc5008
Herwig, Tsokos, Hermanns, Kirkpatrick, Müller, Vascular endothelial cadherin expression in lung specimens of patients with sepsis-induced acute respiratory distress syndrome and endothelial cell cultures, Pathobiology,
doi:10.1159/000347062
Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052
Ivanov, Bartosch, Isaguliants, Oxidative stress in infection and consequent disease, Oxid Med Cell Longev,
doi:10.1155/2017/3496043
Karkhanei, Ghane, Mehri, Evaluation of oxidative stress level: total antioxidant capacity, total oxidant status and glutathione activity in patients with COVID-19, New Microbes New Infect,
doi:10.1016/j.nmni.2021.100897
Kerekes, Arkossy, Altorjay, Huszka, Kappelmayer et al., Evaluation of hemostatic changes and blood antioxidant capacity in acute and chronic pancreatitis, Hepatogastroenterology
Kim, Kim, Ryu, Kim, Park et al., Reactive oxygen species induce antiviral innate immune response through IFN-λ regulation in human nasal epithelial cells, Am J Respir Cell Mol Biol,
doi:10.1165/rcmb.2013-0003OC
Korniluk, Koper-Lenkiewicz, Kamińska, Kemona, Dymicka-Piekarska, Mean platelet volume (MPV): new perspectives for an old marker in the course and prognosis of inflammatory conditions, Mediators Inflamm,
doi:10.1155/2019/9213074
Krause, Geary, Doolen, Duckles, Melatonin and cardiovascular function, Adv Exp Med Biol
Kuba, Imai, Rao, Gao, Guo et al., A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury, Nat Med,
doi:10.1038/nm1267
Lan, Ge, Yu, Shan, Zhou et al., Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor, Nature,
doi:10.1038/s41586-020-2180-5
Liu, Li, Long, Zeng, Gao et al., Bilirubin levels as potential indicators of disease severity in coronavirus disease patients: a retrospective cohort study, Front Med (Lausanne),
doi:10.3389/fmed.2020.598870
Lorente, Martín, Almeida, Abreu-González, Ferreres et al., Association between serum total antioxidant capacity and mortality in severe septic patients, J Crit Care,
doi:10.1016/j.jcrc.2014.09.012
Mariappan, Manoharan, Shanmugam, Rao, Pillai, Potential biomarkers for the early prediction of SARS-COV-2 disease outcome, Microb Pathog,
doi:10.1016/j.micpath.2021.105057
Mariappan, Ranganadin, Shanmugam, Rao, Pillai, Early shedding of membrane-bounded ACE2 could be an indicator for disease severity in SARS-CoV-2, Biochimie,
doi:10.1016/j.biochi.2022.06.005
Mariappan, Rr, Pillai, Angiotensin-converting enzyme 2: a protective factor in regulating disease virulence of SARS-COV-2, IUBMB Life,
doi:10.1002/iub.2391
Muhammad, Kani, Iliya, Muhammad, Binji et al., Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: a cross-sectional comparative study in Jigawa, Northwestern Nigeria SAGE Open Med,
doi:10.1177/2050312121991246
Neoptolemos, Kemppainen, Mayer, Fitzpatrick, Raraty et al., Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide: a multicentre study, Lancet,
doi:10.1016/s0140-6736(00)02327-8
Oostwoud, Gunasinghe, Seow, Ye, Selemidis et al., Apocynin and ebselen reduce influenza A virus-induced lung inflammation in cigarette smoke-exposed mice, Sci Rep,
doi:10.1038/srep20983
Ozdinc, Oz, Ozdemir, Kilic, Karakaya et al., Melatonin: is it an effective antioxidant for pulmonary contusion?, J Surg Res,
doi:10.1016/j.jss.2016.05.020
Paliogiannis, Zinellu, Bilirubin levels in patients with mild and severe Covid-19: a pooled analysis, Liver Int,
doi:10.1111/liv.14477
Rabaan, Sh, Muhammad, Khan, Sule et al., Role of inflammatory cytokines in COVID-19 patients: a review on molecular mechanisms, immune functions immunopathology and immunomodulatory drugs to counter cytokine storm, Vaccines,
doi:10.3390/vaccines9050436
Rieder, Wirth, Pollmeier, Jeserich, Goller et al., Serum ACE2, angiotensin II, and aldosterone levels are unchanged in patients with COVID-19, Am J Hypertens,
doi:10.1093/ajh/hpaa169
Shemies, Nagy, Younis, Sheashaa, Renal replacement therapy for critically ill patients with COVID-19-associated acute kidney injury: a review of current knowledge, Ther Apher Dial,
doi:10.1111/1744-9987.13723
Shereen, Khan, Kazmi, Bashir, Siddique, COVID-19 infection: origin, transmission, and characteristics of human coronaviruses, J Adv Res,
doi:10.1016/j.jare.2020.03.005
Ucar, Korkmaz, Reiter, Yaren, Oter et al., Melatonin alleviates lung damage induced by the chemical warfare agent nitrogen mustard, Toxicol Lett,
doi:10.1016/j.toxlet.2007.07.005
Van Boheemen, De Graaf, Lauber, Bestebroer, Raj et al., Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans,
doi:10.1128/mBio.00473-12
Vieira, Nery, Martins, Jabour, Dias et al., Downregulation of membrane-bound angiotensin converting enzyme 2 (ACE2) receptor has a pivotal role in COVID-19 immunopathology, Curr Drug Targets,
doi:10.2174/1389450121666201020154033
Yaghoubi, Youssefi, Azad, Farzad, Yavari et al., Total antioxidant capacity as a marker of severity of COVID-19 infection: possible prognostic and therapeutic clinical application, J Med Virol,
doi:10.1002/jmv.27500
Yan, Zhang, Li, Xia, Guo et al., Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2, Science,
doi:10.1126/science.abb2762
Zein, Raffaello, Effect of colchicine on mortality in patients with COVID-19-a systematic review and meta-analysis, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2022.102395
Zhong, Peng, Mean platelet volume/platelet count ratio predicts severe pneumonia of COVID-19, J Clin Lab Anal,
doi:10.1002/jcla.23607
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'(2005) A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS '
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'published': {'date-parts': [[2023, 5, 24]]},
'assertion': [ { 'value': '22 January 2023',
'order': 1,
'name': 'received',
'label': 'Received',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '10 May 2023',
'order': 2,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '24 May 2023',
'order': 3,
'name': 'first_online',
'label': 'First Online',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}},
{ 'value': 'The authors declare that they have no conflict of interest to declare.',
'order': 2,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Conflict of interest'}},
{ 'value': 'The study protocol was carried according to Institutional Ethics Committee of '
'Mansoura University, Egypt (approval number sci-Z-ph-2021–60) which performed '
'in compliance with the ethical guidelines outlined in the 1964 Helsinki '
'Declaration. Patients have signed informed consent form.',
'order': 3,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Ethics approval'}},
{ 'value': 'Not applicable.',
'order': 4,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Consent to participate'}},
{ 'value': 'Not applicable.',
'order': 5,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Consent to publish'}}]}