Abstract
In this study, the regulatory mechanisms induced by extracellular hydrogen peroxide were analyzed on the basis of a mathematical model that considers the key stages of the formation of methemoglobin and ferrylhemoglobin, as well as their binding to the erythrocyte membrane. Numerical modeling has shown that reversible binding of methemoglobin to the membrane is an adaptive mechanism aimed at stabilizing the lipid bilayer of the membrane. On the other hand, an increase in the concentration of ferrylhemoglobin and its binding to the membrane leads to an increase in pathophysiological processes that reduce the structural stability of cells. The quantity of methemoglobins and ferrylhemoglobins formed depends on the concentration of extracellular hydrogen peroxide and exposition time, the number of cells in the sample, the state of the antioxidant system of erythrocytes, the metabolic activity of cells and external metabolic conditions. Based on numerical modeling, optimal conditions (oxidant concentration and exposition time) have been determined, under which the activation of adaptive processes occurs. Experiments with erythrocyte hemolysis in vitro have shown that hydrogen peroxide at concentrations of 10–200 μM causes an increase in the structural stability of the membrane and a decrease in the proportion of hemolyzed erythrocytes.
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REFERENCES
Martinovich G.G., Cherenkevich S.N. 2008. Okislitelno-vosstanovitelnie processi v kletkah (Redox processes in cells). Minsk: BSU.
Sies H., Jones D.P. 2020. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 21 (3), 1–21.
Ghezzi P., Jaquet V., Marcucci F., Schmidt H. 2017. The oxidative stress theory of disease: Levels of evidence and epistemological aspects. Br. J. Pharmacol. 174, 1784–1796.
Ursini F., Maiorino M., Forman H.J. 2016. Redox homeostasis: The golden mean of healthy living. Redox Biology. 8, 205–215.
Lim J.B., Huang B.K., Deen W.M., Sikes H.D. 2015. Analysis of the lifetime and spatial localization of hydrogen peroxide generated in the cytosol using a reduced kinetic model. Free Radic. Biol. Med. 89, 47–53.
Johnson R.M., Goyette G.Jr., Ravindranath Y., Ho Y. 2005. Hemoglobin autoxidation and regulation of endogenous H2O2 levels in erythrocytes. Free Radic. Biol. Med. 39, 1407–1417.
Orrico F., Möller M.N., Cassina A., Denicola A., Thomson L. 2018. Kinetic and stoichiometric constraints determine the pathway of H2O2 consumption by red blood cells. Free Radic. Biol. Med. 121, 231–239.
Merry T.L., Ristow M. 2016. Mitohormesis in exercise training. Free Radic. Biol. Med. 98, 123–130. https://doi.org/10.1016/j.freeradbiomed.2015.11.032
Kosmachevskaya O.V., Nasybullina E.I., Blindar V.N., Topunov A.F. 2019. Binding of erythrocyte hemoglobin to the membrane as a way of implementing the signal-regulatory function (review). Applied Biochem. Microbiol. 55 (2), 83–98.
Zenkov N.K., Chechushkov A.V., Kozhin P.M., Kandalintseva N.V., Martinovich G.G., Menshchikova E.B. 2017. Mazes of Nrf2 Regulation. Biochemistry (Moscow). 82 (5), 556–564.
Cuadrado A., Rojo A., Wells G., Hayes J., Cousin S., Rumsey W., Attucks O., Franklin S., Levonen A., Kensler T., Dinkova-Kostova A. 2019. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18, 295–317.
Arashiki N., Kimata N., Manno S., Mohandas N., Takakuwa Y. 2013. Membrane peroxidation and methemoglobin formation are both necessary for band 3 clustering: Mechanistic insights into human erythrocyte senescence. Biochemistry. 52, 5760−5769.
Kuhn V., Diederich L., Stevenson Keller IV T.C., Kramer C.M., Lückstädt W., Panknin C., Suvorava T., Isakson B.E., Kelm M., Cortese-Krott M.M. 2017. Red blood cell function and dysfunction: Redox regulation, nitric oxide metabolism, anemia. Antioxid. Redox Signal. 26 (13), 718–742.
Forman H.J., Bernardo A., Davies K.J.A. 2016. What is the concentration of hydrogen peroxide in blood and plasma? Arch. Biochem. Biophys. 603, 48–53.
Roy S., Khanna S., Nallu K., Hunt T.K., Sen C.K. 2006. Dermal wound healing is subject to redox control. Mol. Ther. 13 (1), 211–220.
Niethammer P., Grabher C., Look A.T., Mitchison T.J. 2009. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature. 459 (7249), 996–999.
Zavodnik I.B., Lapshina E.A., Zavodnik L.B., Soszynski M., Bartosz G., Bryszewska M. 2002. Hypochlorous acid-induced oxidative damage of human red blood cells: Effects of tert-butyl hydroperoxide and nitrite on the HOCl reaction with erythrocytes. Bioelectrochemistry. 58, 127–135.
Liu S., Palek J. 1984. Hemoglobin enhances the self-association of spectrin heterodimers in human erythrocytes. J. Biol. Chem. 259 (18), 11556–11562.
Snyder L.M., Fortier N.L., Trainor J., Jacobs J., Lob L., Lubin B., Chiu D., Shohet S., Mohandas N. 1985. Effect of hydrogen peroxide exposure on normal human erythrocyte deformability, morphology, surface characteristics, and spectrin-hemoglobin cross-linking. J. Clin. Invest. 76, 1971–1977.
Kaul R.K., Köhler H. 1983. Interaction of hemoglobin with Band 3: A review. Klin. Wochenschr. 61, 831–837.
Welbourn E.M., Wilson M.T., Yusof A., Metodiev M.V., Cooper C.E. 2017. The mechanism of formation, structure, and physiological relevance of covalent hemoglobin attachment to the erythrocyte membrane. Free Radic. Biol. Med. 103, 95–106.
Jarolim P., Lahav M., Liu S.C., Palek J. 1990. Effect of hemoglobin oxidation products on the stability of red cell membrane skeletons and the associations of skeletal proteins: Correlation with a release of hemin. Blood. 76. 2125–2131
Nicholls P. 1965. Activity of catalase in the red cell. Biochim. Biophys. Acta. 99, 286–297.
Kinoshita A., Nakayama Y., Kitayama T., Tomita M. 2007. Simulation study of methemoglobin reduction in erythrocytes. Differential contributions of two pathways to tolerance to oxidative stress. FEBS J. 274, 1449–1458.
Rapoport T.A., Heinrich R., Jacobasch G., Rapoport S. 1974. A linear steady-state treatment of enzymatic chains. A mathematical model of glycolysis of human erythrocytes. Eur. J. Biochem. 42, 107–120.
Ataullakhanov F.I., Vitvitsky V.M., Jabotinsky A.M., 1977. Quantitative model of human erythrocytes glycolysis. Biofizika (Rus.). 22 (3), 483–488.
Mulquiney P.J., Kuchel P.W. 1999. Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: Equations and parameter refinement. Biochem. J. 342, 581–596.
Martinovich G.G., Cherenkevich S.N. 2005. Consumption of intracellular hydrogen peroxide in epithelial human amnion cells. Biomeditsinskaya Khimiya (Rus.). 51 (6), 626–633.
Lipunova E.A., Skorkina M.Yu. 2004. Sistema krasnoy krovi: Sravnitelnaya fiziologoya (The red blood system: Comparative physiology). Belgorod: BelSU Publishing House.
Gebicka L., Banasiak E. 2009 Flavonoids as reductants of ferryl hemoglobin. Acta Biochim. Pol. 56 (3) 509–513.
Peng Xu D., Washburn M.P., Ping Sun G. Wells W. 1996. Purification and characterization of a glutathione dependent dehydroascorbate reductase from human erythrocytes. Biochem. Biophys. Res. Commun. 221 (1), 117–121.
Bali M., Thomas S.R. 2001. A modelling study of feedforward activation in human erythrocyte glycolysis. C.R. Acad. Sci. III. 324, 185–199.
Cherenkevich S.N., Martinovich G.G., Khmelnitsky A.I. 2008. Biologicheskie membrany (Biological membranes). Minsk: BSU.
Miłek J. 2018. Estimation of the kinetic parameters for H2O2 enzymatic decomposition and for catalase deactivation. Braz. J. Chem. Eng. 35 (3), 995–1004.
Benfeitas R., Selvaggio G., Antunes F., Coelho P.M.B.M., Salvador A. 2014. Hydrogen peroxide metabolism and sensing in human erythrocytes: A validated kinetic model and reappraisal of the role of peroxiredoxin II. Free Radic. Biol. Med. 74, 35–49.
Kanias T., Acker J.P. 2010. Biopreservation of red blood cells – the struggle with hemoglobin oxidation. FEBS J. 277, 343–356.
May J.M., Qu Z., Cobb C.E. 2004. Human erythrocyte recycling of ascorbic acid. J. Biol. Chem. 279 (15), 14975–14982.
Martinovich G.G., Sazanov L.A., Cherenkevich S.N. 2017. Kletochnaya bioenergetika: Fiziko-khimicheskie i molekularnie osnovy (Cellular bioenergetics: Physico-chemical and molecular basis). M.: LENAND.
Jaffe E.R. 1963. The reduction of methemoglobin in erythrocytes of a patient with congenital methemoglobinemia, subjects with erythrocyte glucose-6-phosphate dehydrogenase deficiency, and normal individuals. Blood. 21 (5), 561–572.
Mendanha S.A., Anjos J.L.V., Silva A.H.M., Alonso A. 2012. Electron paramagnetic resonance study of lipid and protein membrane components of erythrocytes oxidized with hydrogen peroxide. Braz. J. Med. Biol. Res. 45, 473–481.
Kassa T., Jana S., Meng F., Alayash A.I. 2016. Differential heme release from various hemoglobin redox states and the upregulation of cellular heme oxygenase-1. FEBS Open Bio. 6, 876–884.
ACKNOWLEDGMENTS
The work was partially supported by the Belarusian Republican Foundation for Basic Research (project no. B20U-1).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants involved in the study.
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APPENDIX
APPENDIX
The system of differential equations used in this study is presented below. In this form, the system was presented in the Wolfram Mathematica software.
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Voinarouski, V.V., Martinovich, G.G. Regulation of the Structural Stability of Erythrocytes by Hydrogen Peroxide: Mathematical Model and Experiment. Biochem. Moscow Suppl. Ser. A 16, 91–105 (2022). https://doi.org/10.1134/S1990747822010093
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DOI: https://doi.org/10.1134/S1990747822010093