Upregulation of MicroRNA-144 Suppresses Nrf2 Antioxidant Signaling Pathway in Patients with Severe COVID-19
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Abstract
MicroRNAs (miRs) play a pivotal role in the pathogenesis of viral infections. It has been proven that the Nrf2 (NFE2 like bZIP transcription factor 2) antioxidant signaling pathway is inhibited in COVID-19 patients. Two microRNAs (MIR144 and MIR153-1) have been identified as important Nrf2 regulators. The aim of this study was to analyze the MIR144 and MIR153-1 expression in COVID-19 patients and investigate their association with the Nrf2 signaling pathway.
The study had 82 participants with both mild and severe COVID-19 manifestations and 25 healthy as a control group. Ficoll density-gradient centrifugation was used to separate peripheral blood mononuclear cells from ethylenediaminetetraacetic acid blood tubes. MIR144, MIR153-1, and NFE2L2 expressions were studied using real-time polymerase chain reaction. We employed the commercially available enzyme-linked immunosorbent assay to measure plasma Nrf2 protein concentration and the activity of antioxidant enzymes, superoxide dismutase, and catalase.
Compared to the control group, MIR144 expression was significantly increased in the severe group, while NFE2L2 expression decreased. There was no significant difference in the MIR153-1 expression rate between COVID-19 patients and controls. Nrf2 protein and antioxidant enzyme activity significantly decreased in the severe group. A negative correlation between MIR144 expression and Nrf2 protein concentration was observed.
Taken together, the current study's findings showed that MIR144 upregulation probably interferes with the Nrf2 antioxidant signaling pathway in COVID-19 patients.
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9. Fan X, Staitieh BS, Jensen JS, Mould KJ, Greenberg JA, Joshi PC, et al. Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats. Am J Physiol Lung Cell Mol Physiol. 2013;305(3):L267-L77.
10. Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, et al. Interplay between miRNAs and human diseases. J Cell Physiol. 2018;233(3):2007-18.
11. Tan L, Yu J-T, Tan L. Causes and consequences of microRNA dysregulation in neurodegenerative diseases. Mol Neurobiol. 2015;51:1249-62.
12. Mohammed CPD, Park JS, Nam HG, Kim K. MicroRNAs in brain aging. Mech Ageing Dev. 2017;168:3-9.
13. Vishnoi A, Rani S. MiRNA biogenesis and regulation of diseases: an overview. Methods Mol Biol. 2017:1-10.
14. Guo Y, Yu S, Zhang C, Kong A-NT. Epigenetic regulation of Keap1-Nrf2 signaling. Free Radic Biol Med. 2015;88:337-49.
15. Joshi PC, Raynor R, Fan X, Guidot DM. HIV-1–transgene expression in rats decreases alveolar macrophage zinc levels and phagocytosis. Am J Respir Cell Mol Biol. 2008;39(2):218-26.
16. Lassiter C, Fan X, Joshi PC, Jacob BA, Sutliff RL, Jones DP, et al. HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction. AIDS Res Ther. 2009;6(1):1-12.
17. Li Y, Zhao Y, Cheng M, Qiao Y, Wang Y, Xiong W, et al. Suppression of microRNA‐144‐3p attenuates oxygen–glucose deprivation/reoxygenation‐induced neuronal injury by promoting Brg1/Nrf2/ARE signaling. J Biochem Mol Toxicol. 2018;32(4):e22044.
18. Lu MC, Ji JA, Jiang ZY, You QD. The Keap1–Nrf2–ARE pathway as a potential preventive and therapeutic target: an update. Med Res Rev. 2016;36(5):924-63.
19. Marts LT, Green DE, Mills ST, Murphy T, Sueblinvong V. MiR‐21‐Mediated Suppression of Smad7 Induces TGF β1 and Can Be Inhibited by Activation of Nrf2 in Alcohol‐Treated Lung Fibroblasts. Cli Exp Res. 2017;41(11):1875-85.
20. Mai F, Del Pinto R, Ferri C. COVID-19 and cardiovascular diseases. J Cardiol. 2020;76(5):453-8.
21. Hou W, Zhu X, Liu J, Map J. Inhibition of miR-153 ameliorates ischemia/reperfusion-induced cardiomyocytes apoptosis by regulating Nrf2/HO-1 signaling in rats. Biomed Engine online. 2020;19:1-14.
22. Zhu J, Wang S, Qi W, Xu X, Liang Y. Overexpression of miR-153 promotes oxidative stress in MPP+-induced PD model by negatively regulating the Nrf2/HO-1 signaling pathway. Int J Clin Exp Pathol. 2018;11(8):4179.
23. Yang P, Yang Y, He X, Sun P, Zhang Y, Song X, et al. miR-153-3p targets βII spectrin to regulate formaldehyde-induced cardiomyocyte apoptosis. Front Cardiovascular Med. 2021;8:764831.
24. Ning W, Li S, Yang W, Yang B, Xin C, Ping X, et al. Blocking exosomal miRNA-153-3p derived from bone marrow mesenchymal stem cells ameliorates hypoxia-induced myocardial and microvascular damage by targeting the ANGPT1-mediated VEGF/PI3k/Akt/eNOS pathway. Cell Signalling. 2021;77:109812.
25. Sodagar H, Ansari MHK, Asghari R, Alipour S. Evaluation of Serum Levels of MicroRNA-200C and ACE2 Gene Expression in Severe and Mild Phases of Patients with COVID-19. Iran J Allergy, Asthma and Immunology. 2022.
26. Soin AS, Kumar K, Choudhary NS, Sharma P, Mehta Y, Kataria S, et al. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Resp Me. 2021;9(5):511-21.
27. Gustine JN, Jones D. Immunopathology of Hyperinflammation in COVID-19. Am J Pathol. 2021;191(1):4-17.
28. Tufan A, Güler AA, Matucci-Cerinic M. COVID-19, immune system response, hyperinflammation and repurposingantirheumatic drugs. Turkish journal of medical sciences. 2020;50(9):620-32.
29. Taher A, Lashgari M, Sedighi L, Rahimi-Bashar F, Poorolajal J, Mehrpooya M. A pilot study on intravenous N-Acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome. Pharmacol Rep. 2021;73(6):1650-9.
30. Delgado-Roche L, Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res. 2020;51(5):384-7.
31. Olagnier D, Farahani E, Thyrsted J, Blay-Cadanet J, Herengt A, Idorn M, et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. 2020;11(1):4938.
32. Kukoyi AT, Fan X, Staitieh BS, Hybertson BM, Gao B, McCord JM, et al. MiR-144 mediates Nrf2 inhibition and alveolar epithelial dysfunction in HIV-1 transgenic rats. Am J Physiology-Cell Physiol. 2019;317(2):C390-C7.
33. Bansal M. Cardiovascular disease and COVID-19. Diabetes Metab Syndr. 2020;14(3):247-50.
2. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013;53:401-26.
3. Liu Q, Gao Y, Ci X. Role of Nrf2 and its activators in respiratory diseases. Oxid Med Cell Longev. 2019;2019.
4. Mizumura K, Maruoka S, Shimizu T, Gon Y. Role of Nrf2 in the pathogenesis of respiratory diseases. Resp Invest. 2020;58(1):28-35.
5. Herengt A, Thyrsted J, Holm CK. NRF2 in viral infection. Antioxidants. 2021;10(9):1491.
6. Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, Kensler TW, et al. Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice. J Clin Invest. 2004;114(9):1248-59.
7. Suzuki M, Betsuyaku T, Ito Y, Nagai K, Nasuhara Y, Kaga K, et al. Down-regulated NF-E2–related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am J Resp Cell Mol Biol. 2008;39(6):673-82.
8. Rahman MS, Alam MB, Kim YK, Madina MH, Fliss I, Lee SH, et al. Activation of nrf2/ho-1 by peptide yd1 attenuates inflammatory symptoms through suppression of tlr4/myyd88/nf-κb signaling cascade. Int J Mol Sci. 2021;22(10):5161.
9. Fan X, Staitieh BS, Jensen JS, Mould KJ, Greenberg JA, Joshi PC, et al. Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats. Am J Physiol Lung Cell Mol Physiol. 2013;305(3):L267-L77.
10. Paul P, Chakraborty A, Sarkar D, Langthasa M, Rahman M, Bari M, et al. Interplay between miRNAs and human diseases. J Cell Physiol. 2018;233(3):2007-18.
11. Tan L, Yu J-T, Tan L. Causes and consequences of microRNA dysregulation in neurodegenerative diseases. Mol Neurobiol. 2015;51:1249-62.
12. Mohammed CPD, Park JS, Nam HG, Kim K. MicroRNAs in brain aging. Mech Ageing Dev. 2017;168:3-9.
13. Vishnoi A, Rani S. MiRNA biogenesis and regulation of diseases: an overview. Methods Mol Biol. 2017:1-10.
14. Guo Y, Yu S, Zhang C, Kong A-NT. Epigenetic regulation of Keap1-Nrf2 signaling. Free Radic Biol Med. 2015;88:337-49.
15. Joshi PC, Raynor R, Fan X, Guidot DM. HIV-1–transgene expression in rats decreases alveolar macrophage zinc levels and phagocytosis. Am J Respir Cell Mol Biol. 2008;39(2):218-26.
16. Lassiter C, Fan X, Joshi PC, Jacob BA, Sutliff RL, Jones DP, et al. HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction. AIDS Res Ther. 2009;6(1):1-12.
17. Li Y, Zhao Y, Cheng M, Qiao Y, Wang Y, Xiong W, et al. Suppression of microRNA‐144‐3p attenuates oxygen–glucose deprivation/reoxygenation‐induced neuronal injury by promoting Brg1/Nrf2/ARE signaling. J Biochem Mol Toxicol. 2018;32(4):e22044.
18. Lu MC, Ji JA, Jiang ZY, You QD. The Keap1–Nrf2–ARE pathway as a potential preventive and therapeutic target: an update. Med Res Rev. 2016;36(5):924-63.
19. Marts LT, Green DE, Mills ST, Murphy T, Sueblinvong V. MiR‐21‐Mediated Suppression of Smad7 Induces TGF β1 and Can Be Inhibited by Activation of Nrf2 in Alcohol‐Treated Lung Fibroblasts. Cli Exp Res. 2017;41(11):1875-85.
20. Mai F, Del Pinto R, Ferri C. COVID-19 and cardiovascular diseases. J Cardiol. 2020;76(5):453-8.
21. Hou W, Zhu X, Liu J, Map J. Inhibition of miR-153 ameliorates ischemia/reperfusion-induced cardiomyocytes apoptosis by regulating Nrf2/HO-1 signaling in rats. Biomed Engine online. 2020;19:1-14.
22. Zhu J, Wang S, Qi W, Xu X, Liang Y. Overexpression of miR-153 promotes oxidative stress in MPP+-induced PD model by negatively regulating the Nrf2/HO-1 signaling pathway. Int J Clin Exp Pathol. 2018;11(8):4179.
23. Yang P, Yang Y, He X, Sun P, Zhang Y, Song X, et al. miR-153-3p targets βII spectrin to regulate formaldehyde-induced cardiomyocyte apoptosis. Front Cardiovascular Med. 2021;8:764831.
24. Ning W, Li S, Yang W, Yang B, Xin C, Ping X, et al. Blocking exosomal miRNA-153-3p derived from bone marrow mesenchymal stem cells ameliorates hypoxia-induced myocardial and microvascular damage by targeting the ANGPT1-mediated VEGF/PI3k/Akt/eNOS pathway. Cell Signalling. 2021;77:109812.
25. Sodagar H, Ansari MHK, Asghari R, Alipour S. Evaluation of Serum Levels of MicroRNA-200C and ACE2 Gene Expression in Severe and Mild Phases of Patients with COVID-19. Iran J Allergy, Asthma and Immunology. 2022.
26. Soin AS, Kumar K, Choudhary NS, Sharma P, Mehta Y, Kataria S, et al. Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet Resp Me. 2021;9(5):511-21.
27. Gustine JN, Jones D. Immunopathology of Hyperinflammation in COVID-19. Am J Pathol. 2021;191(1):4-17.
28. Tufan A, Güler AA, Matucci-Cerinic M. COVID-19, immune system response, hyperinflammation and repurposingantirheumatic drugs. Turkish journal of medical sciences. 2020;50(9):620-32.
29. Taher A, Lashgari M, Sedighi L, Rahimi-Bashar F, Poorolajal J, Mehrpooya M. A pilot study on intravenous N-Acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome. Pharmacol Rep. 2021;73(6):1650-9.
30. Delgado-Roche L, Mesta F. Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res. 2020;51(5):384-7.
31. Olagnier D, Farahani E, Thyrsted J, Blay-Cadanet J, Herengt A, Idorn M, et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun. 2020;11(1):4938.
32. Kukoyi AT, Fan X, Staitieh BS, Hybertson BM, Gao B, McCord JM, et al. MiR-144 mediates Nrf2 inhibition and alveolar epithelial dysfunction in HIV-1 transgenic rats. Am J Physiology-Cell Physiol. 2019;317(2):C390-C7.
33. Bansal M. Cardiovascular disease and COVID-19. Diabetes Metab Syndr. 2020;14(3):247-50.
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| Section | Coronavirus Disease (COVID-19)-Original Article | |
| Keywords | ||
| COVID-19 MIR153-1 MIR144 Nrf2 Signaling pathway | ||
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How to Cite
1.
Nasirzadeh M, Pouramir M, Gholizadeh-Ghaleh Aziz S, Alipour S. Upregulation of MicroRNA-144 Suppresses Nrf2 Antioxidant Signaling Pathway in Patients with Severe COVID-19. Iran J Allergy Asthma Immunol. 2024;:1-10.
