Mechanisms of antioxidant protection of low-density lipoprotein particles against free radical oxidation
- Authors: Lankin V.Z.1, Shumaev K.B.1,2, Medvedeva V.A.1, Tikhaze A.K.1, Konovalova G.G.1
-
Affiliations:
- National Medical Research Center of Cardiology Named after Academician E. I. Chazov, Ministry of Health of the Russian Federation
- Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences
- Issue: Vol 90, No 1 (2025)
- Pages: 117-130
- Section: Articles
- URL: https://rjeid.com/0320-9725/article/view/682181
- DOI: https://doi.org/10.31857/S0320972525010087
- EDN: https://elibrary.ru/CPLPQB
- ID: 682181
Cite item
Abstract
It was found that when patients with atherosclerosis are orally administered ubiquinon Q10 (CoQ10), the oxidation (lipohydroperoxide content) of low-density lipoprotein (LDL) particles sharply decreases, which confirms the important role of this natural antioxidant in protecting LDL particles from free radical oxidation in vivo. The influence of lipophilic natural antioxidants ubiquinol Q10 (CoQ10H2) and α-tocopherol (α-TOH) on the kinetic parameters of Cu2+-initiated free radical oxidation of LDL particles was investigated. In this model system, the possible synergism of the antioxidant action of CoQ10H2 and α-TOH is shown. The probable mechanisms of bioregeneration of the lipophilic antioxidants in LDL particles, including regeneration of α-TOH from the tocopheroxyl radical (α-TO•) with the participation of CoQ10H2 and/or ascorbate, are discussed.
Full Text

About the authors
V. Z. Lankin
National Medical Research Center of Cardiology Named after Academician E. I. Chazov, Ministry of Health of the Russian Federation
Author for correspondence.
Email: lankin0309@mail.ru
Russian Federation, 121552 Moscow
K. B. Shumaev
National Medical Research Center of Cardiology Named after Academician E. I. Chazov, Ministry of Health of the Russian Federation; Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences
Email: lankin0309@mail.ru
Russian Federation, 121552 Moscow; 119071 Moscow
V. A. Medvedeva
National Medical Research Center of Cardiology Named after Academician E. I. Chazov, Ministry of Health of the Russian Federation
Email: lankin0309@mail.ru
Russian Federation, 121552 Moscow
A. K. Tikhaze
National Medical Research Center of Cardiology Named after Academician E. I. Chazov, Ministry of Health of the Russian Federation
Email: lankin0309@mail.ru
Russian Federation, 121552 Moscow
G. G. Konovalova
National Medical Research Center of Cardiology Named after Academician E. I. Chazov, Ministry of Health of the Russian Federation
Email: lankin0309@mail.ru
Russian Federation, 121552 Moscow
References
- Sharapov, M. G., Gudkov, S. V., and Lankin, V. Z. (2021) Hydroperoxide reducing enzymes in the regulation of free radical processes, Biochemistry (Moscow), 86, 1256-1274, https://doi.org/10.1134/S0006297921100084.
- Shen, B. W., Scanu, A. M., and Kezdy, F. J. (1977) Structure of human serum lipoproteins inferred from compositional analysis, Proc. Natl. Acad. Sci. USA, 74, 837-841, https://doi.org/10.1073/pnas.74.3.837.
- Lankin, V. Z., Tikhaze, A. K., and Kosach, V. Ya. (2022) Comparative susceptibility to oxidation of different classes of blood plasma lipoproteins, Biochemistry (Moscow), 87, 1335-1341, https://doi.org/10.1134/S0006297922110128.
- Sharapov, M. G., Gudkov, S. V., and Lankin, V. Z. (2021) Role of glutathione peroxidases and peroxiredoxins in free radical induced pathologies, Biochemistry (Moscow), 86, 1418-1433, https://doi.org/10.1134/S0006297921110067.
- Lankin, V. Z., and Tikhaze, A. K. (2017) Role of oxidative stress in the genesis of atherosclerosis and diabetes mellitus: a personal look back on 50 years of research, Curr. Aging Sci., 10, 18-25, https://doi.org/10.2174/1874609809666160926142640.
- Mellors, A., and Tappel, A. L. (1966) The inhibition of mitochondrial peroxidation by ubiquinone and ubiquinol, J. Biol. Chem., 241, 4353-4356, https://doi.org/10.1016/S0021-9258(18)99728-0.
- Witting, L. A. (1980) Vitamin E and lipid antioxidants in free-radical-initiated reactions, Free Radic. Biol., 4, 295-319, https://doi.org/10.1016/B978-0-12-566504-9.50016-7.
- Bliznakov, E. G., and Wilkins, D. J. (1998) Biochemical and clinical consequences of inhibiting coenzyme Q10 biosynthesis by lipid-lowering HMG-CoA reductase inhibitors (statins): a critical overview, Adv. Ther., 15, 218-228.
- Hevonoja, T., Pentikäinen, M. O., Hyvönen, M. T., Kovanen, P. T., and Ala-Korpela, M. (2000) Structure of low density lipoprotein (LDL) particles: basis for understanding molecular changes in modified LDL, Biochim. Biophys. Acta., 15, 189-210, https://doi.org/10.1016/s1388-1981(00)00123-2.
- Thomas, S. R., Neuzil, J., and Stocker, R. (1997) Inhibition of LDL oxidation by ubiquinol-10. A protective mechanism for coenzyme Q in atherogenesis? Mol. Aspects Med., 18, 85-103, https://doi.org/10.1016/s0098-2997(97)00031-9.
- Thomas, S. R., Witting, P. K., and Stocker, R. (1999) A role for reduced coenzyme Q in atherosclerosis? Biofactors, 9, 207-224, https://doi.org/10.1002/biof.5520090216.
- Littarru, G. P., Battino, M., Tomasetti, M., Mordente, A., Santini, S., Oradei, A., Manto, A., and Ghirlanda, G. (1994) Metabolic implications of coenzyme Q10 in red blood cells and plasma lipoproteins, Mol. Aspects Med., 15, 67-72, https://doi.org/10.1016/0098-2997(94)90014-0.
- Stocker, R. (1993) Natural antioxidants and atherosclerosis, Asia Pac. J. Clin. Nutr., 2, 15-20.
- Niki, E. (2014) Role of vitamin E as a lipid-soluble peroxyl radical scavenger: in vitro and in vivo evidence, Free Radic. Biol. Med., 66, 3-12, https://doi.org/10.1016/j.freeradbiomed.2013.03.022.
- Frei, B., Kim, M. C., and Ames, B. N. (1990) Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations, Proc. Natl. Acad. Sci. USA, 87, 4879-4883, https://doi.org/10.1073/pnas.87.12.4879.
- Kagan, V. E., Fabisiak, J. E., and Quinn, E. J. (2000) Coenzyme Q and vitamin E need each other as antioxidants, Protoplasma, 214, 11-18, https://doi.org/10.1007/BF02524257.
- Bowry, V. W., Stocker, R. (1993) Tocopherol-mediated peroxidation. The prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein, J. Am. Chem. Soc., 115, 6029-6044, https://doi.org/10.1021/ja00067a019.
- Witting, P. K., Upston, J. M., and Stocker, R. (1997) Role of alpha-tocopheroxyl radical in the initiation of lipid peroxidation in human low-density lipoprotein exposed to horse radish peroxidase, Biochemistry, 36, 1251-1258, https://doi.org/10.1021/bi962493j.
- Fong, C. W. (2023) Coenzyme Q 10 and Vitamin E synergy, electron transfer, antioxidation in cell membranes, and interaction with cholesterol, hal-03976270.
- Lindgren, F. T. (1975) Preparative ultracentrifugal laboratory procedures and suggestions for lipoprotein analysis, in Analysis of Lipids and Lipoproteins (Perkins, E. G., ed) Champaign: Amer. Oil. Chemists Soc., pp. 204-224.
- Nourooz-Zadeh, J., Tajaddini-Sarmadi, J., and Wolf, S. P. (1994) Measurement of plasma hydroperoxide concentrations by the ferrous oxidation-xylenol orange assay in conjunction with triphenylphosphine, Anal. Biochem., 220, 403-409, https://doi.org/10.1006/abio.1994.1357.
- Lankin, V. Z., Konovalova, G. G., Tikhaze, A. K., Shumaev, K. B., Kumskova, E. M., and Viigimaa, M. (2014) The initiation of the free radical peroxidation of low-density lipoproteins by glucose and its metabolite methylglyoxal: a common molecular mechanism of vascular wall injures in atherosclerosis and diabetes, Mol. Cell. Biochem., 395, 241-252, https://doi.org/10.1007/s11010-014-2131-2.
- Mark, J., and Burkitt, A. (2001) Critical overview of the chemistry of copper-dependent low density lipoprotein oxidation: roles of lipid hydroperoxides, a-tocopherol, thiols, and ceruloplasmin, Arch. Biochem. Biophys., 394, 117-135, https://doi.org/10.1006/abbi.2001.2509.
- Patel, R. P., and Darley-Usmar, V. (1999) Molecular mechanisms of the copper dependent oxidation of low-density lipoprotein, Free Radic. Res., 30, 1-9, https://doi.org/10.1080/10715769900300011.
- Kontush, A., Hubner, C., Finckh, B., Kohlschutter, A., and Beisiegel, U. (1994) Low density lipoprotein oxidizability by copper correlates to its initial ubiquinol-10 and polyunsaturated fatty acid content, FEBS Lett., 341, 69-73, https://doi.org/10.1016/0014-5793(94)80242-4.
- Эмануэль Н. М., Денисов Е. Т., Майзус З. К. (1965) Цепные реакции окисления углеводородов в жидкой фазе, Москва, Наука, 375 с.
- Kagan, V. E., Freisleben, H. J., Tsuchiya, M., Forte, T., and Packer, L. (1991) Generation of probucol radicals and their reduction by ascorbate and dihydrolipoic acid in human low density lipoproteins, Free Radic. Res. Commun., 15, 265-276, https://doi.org/10.3109/10715769109105222.
- Shumaev, K. B., Ruuge, E. K., Dmitrovsky, A. A., Bykhovsky, V. Ya., and Kukharchuk, V. V. (1997) Effect of lipid peroxidation products and antioxidants on the formation of probucol radical in low density lipoproteins, Biochemistry (Moscow), 62, 657-660.
- Nohl, H., Gille, L., and Kozlov, A. V. (1998) Antioxidant-derived prooxidant formation from ubiquinol, Free Radic. Biol. Med., 25, 666-675, https://doi.org/10.1016/S0891-5849(98)00105-1.
- Roginsky, V. A., Mohr, D., and Stocker, R. (1996) Reduction of ubiquinone-1 by ascorbic acid is a catalytic and reversible process controlled by the concentration of molecular oxygen, Redox Rep., 2, 55-62, https://doi.org/10.1080/13510002.1996.11747027.
- Steinberg, D., Parthasarathy, S., Carew, T. E., Khoo, J. C., and Witztum, J. L. (1989) Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity, New Eng. J. Med., 320, 915-924, https://doi.org/10.1056/NEJM198904063201407.
- Kita, T., Ishii, K., Yokode, M., Kume, N., Nagano, Y., Arai, H., Arai, H., and Kawai, C. (1990) The role of oxidized low density lipoprotein in the pathogenesis of atherosclerosis, Eur. Heart J., 11, 122-127, https://doi.org/10.1093/eurheartj/11.suppl_e.122.
- Witztum, J. L. (1994) The oxidation hypothesis of atherosclerosis, Lancet, 344, 793-795, https://doi.org/10.1016/S0140-6736(94)92346-9.
- Yla-Herttuala, S. (1994) Role of lipid and lipoprotein oxidation in the pathogenesis of atherosclerosis, Drugs Today, 30, 507-514.
- Steinberg, D. (1995) Role of oxidized LDL and antioxidants in atherosclerosis, Adv. Exp. Med. Biol., 369, 39-48, https://doi.org/10.1007/978-1-4615-1957-7_5.
- Lankin, V. Z., and Tikhaze, A. K. (2017) Role of oxidative stress in the genesis of atherosclerosis and diabetes mellitus: a personal look back on 50 years of research, Curr. Aging Sci., 10, 18-25, https://doi.org/10.2174/1874609809666160926142640.
- Lankin, V. Z., Tikhaze, A. K., and Melkumyants, A. M. (2022) Dicarbonyl-dependent modification of LDL as a key factor of endothelial dysfunction and atherosclerotic vascular wall damage, Antioxidants, 11, 1565, https://doi.org/10.3390/antiox11081565.
- Lankin, V. Z., Tikhaze, A. K., and Melkumyants, A. M. (2022) Malondialdehyde as an important key factor of molecular mechanisms of vascular wall damage under heart diseases development, Int. J. Mol. Sci., 24, 128, https://doi.org/10.3390/ijms24010128.
- Lankin, V. Z., Tikhaze, A. K., Sharapov, M. G., and Konovalova, G. G. (2024) The role of natural low molecular weight dicarbonyls in atherogenesis and diabetogenesis, Rev. Cardiovasc. Med., 25, 295, https://doi.org/10.31083/j.rcm2508295.
- Lankin, V. Z., Tikhaze, A. K., and Konovalova, G. G. (2023) Differences in structural changes and pathophysiological effects of low-density lipoprotein particles upon accumulation of acylhydroperoxy derivatives in their outer phospholipid monolayer or upon modification of apoprotein B-100 by natural dicarbonyls, Biochemistry (Moscow), 88, 1910-1919, https://doi.org/10.1134/S0006297923110196.
- Lankin, V. Z., Sharapov, M. G., Tikhaze, A. K., Goncharov, R. G., Antonova, O. A., Konovalova, G. G., and Novoselov, V. I. (2023) Dicarbonyl-modified low-density lipoproteins are key inducers of LOX-1 and NOX1 gene expression in the cultured human umbilical vein endotheliocytes, Biochemistry (Moscow), 88, 2125-2136, https://doi.org/10.1134/S0006297923120143.
- Stocker, R., Bowry, V. W., and Frei, B. (1991) Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does α-tocopherol, Proc. Natl. Acad. Sci. USA, 88, 1646-1650, https://doi.org/10.1073/pnas.88.5.1646.
- Ahmadvand, H., Mabuchi, H., Nohara, A., Kobayahi, J., and Kawashiri, M. A. (2013) Effects of coenzyme Q(10) on LDL oxidation in vitro, Acta Med. Iran, 51, 12-18.
- Raizner, A. E. (2019) Coenzyme Q10, Methodist Debakey Cardiovasc. J., 15,185-191, https://doi.org/10.14797/mdcj-15-3-185.
- Mohr, D., Bowry, V. W., and Stocker, R. (1992) Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation, Biochim. Biophys. Acta, 1126, 247-254, https://doi.org/10.1016/0005-2760(92)90237-P.
- Bargossi, A. M., Grossi, G., Fiorella, P. L., Gaddi, A., Di Giulio, R., and Battino, M. (1994) Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors, Mol. Aspects Med., 15, 187-193, https://doi.org/10.1016/0098-2997(94)90028-0.
- Garrido-Maraver, J., Cordero, M. D., Oropesa-Avila, M., Vega, A.F., de la Mata, M., Pavon A. D., Alcocer-Gomez, E., Calero, C. P., Paz, M. V., Alanis, M., de Lavera, I., Cotan, D., and Sanchez-Alcazar, J. A. (2014) Clinical applications of coenzyme Q10, Front. Biosci., 19, 619-633, https://doi.org/10.2741/4231.
- Gutierrez-Mariscal, F. M., de la Cruz-Ares, S., Torres-Peña, J. D., Alcalá-Diaz, J. F., Yubero-Serrano, E. M., and López-Miranda, J. (2021) Coenzyme Q10 and Cardiovascular diseases, Antioxidants, 10, 906, https://doi.org/10.3390/antiox10060906.
- Lankin, V. Z., and Tikhaze, A. K. (2003) Atherosclerosis as a free radical pathology and antioxidative therapy of this disease, Free Radic., 344, 218-231.
- Lankin, V. Z., Tikhaze, A. K., Kapel’ko, V. I., Shepel’kova, G. S., Shumaev, K. B., Panasenko, O. M., Konovalova, G. G., and Belenkov, Y. N. (2007) Mechanisms of oxidative modification of low density lipoproteins under conditions of oxidative and carbonyl stress, Biochemistry (Moscow), 72, 1081-1090, https://doi.org/10.1134/s0006297907100069.
- Kontush, A., Reich, A., Baum, K., Spranger, T., Finckh, B., Kohlschȕtter, A., and Beisiegel, U. (1997) Plasma ubiquinol-10 is decreased in patients with hyperlipidaemia, Atherosclerosis, 129, 119-126, https://doi.org/10.1016/s0021-9150(96)06021-2.
- Miura, S., Watanabe, J., Tomita, T., Sano, M., and Tomita, I. (1994) The inhibitory effects of tea polyphenols (flavan-3-ol derivatives) on Cu2+-mediated oxidative modification of low density lipoprotein, Biol. Pharm. Bull., 17, 1567-1572, https://doi.org/10.1248/bpb.17.1567.
- Yeomans, V. C., Linseisen, J., and Wolfram, G. (2005) Interactive effects of polyphenols, tocopherol and ascorbic acid on the Cu2+-mediated oxidative modification of human low density lipoproteins, Eur. J. Nutr., 44, 422-428, https://doi.org/10.1007/s00394-005-0546-y.
- Jayaraman, S., Gantz, D. L., Gursky, O. (2007) Effects of oxidation on the structure and stability of human low-density lipoprotein, Biochemistry, 46, 5790-5797, https://doi.org/10.1021/bi700225a.
- Beyer, R. E. (1994) The role of ascorbate in antioxidant protection of biomembranes: interaction with vitamin E and coenzyme Q, J. Bioenerg. Biomembr., 26, 349-358, https://doi.org/10.1007/BF00762775.
- Neuzil, J., Thomas, S. R., and Stocker, R. (1997) Requirement for, promotion, or inhibition by alpha-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation, Free Radic Biol. Med., 22, 57-71, https://doi.org/10.1016/s0891-5849(96)00224-9.
- Carr, A. C., Zhu, B. Z., and Frei, B. (2000) Potential antiatherogenic mechanisms of ascorbate (vitamin C) and alpha-tocopherol (vitamin E), Circ. Res., 87, 349-354, https://doi.org/10.1161/01.res.87.5.349.
- Guo, Q., and Packer, L. (1999) ESR studies of ascorbic acid-dependent recycling of the vitamin E homologue Trolox by coenzyme Q0 in murine skin homogenates, Redox Rep., 4, 105-111, https://doi.org/10.1179/135100099101534783.
- Chancharme, L., Thérond, P., Nigon, F., Zarev, S., Mallet, A., Bruckert, E., and Chapman, M. J. (2002) LDL particle subclasses in hypercholesterolemia. Molecular determinants of reduced lipid hydroperoxide stability, J. Lipid Res., 43, 453-462, https://doi.org/10.1016/S0022-2275(20)30152-8.
Supplementary files
