Oxidized low-density lipoproteins and their contribution to atherosclerosis

Abstract

Lipoprotein oxidation is a critical early stage in the development of atherosclerosis, a disease characterized by the formation of plaque in arterial walls. It has been well-established that the oxidation of low-density lipoprotein (LDL) is a key factor in the progression of atherosclerosis. Oxidized LDL (Ox-LDL) possesses a range of atherogenic properties, contributing to endothelial dysfunction, foam cell formation, and inflammation within the arterial wall. The interaction between Ox-LDL and specific receptors on endothelial cells plays a crucial role in these processes. In this article, we will discuss the oxidation of LDL and the pro-atherogenic role of Ox-LDL, we will delve into the different types of LDL receptors involved in the uptake and metabolism of LDL, with a focus on their role in atherosclerosis. We will explore the mechanisms by which native LDL (nLDL) and Ox-LDL interact with these receptors, leading to the development and progression of atherosclerotic plaques. Then we will go through more in-depth discussion to explore the intricate role of scavenger receptors in the uptake of oxidized low-density lipoproteins (Ox-LDL) and their significant contribution to the pathogenesis of atherosclerosis. Understanding the intricacies of these receptor-ligand interactions is essential for developing targeted therapeutic strategies to combat atherosclerosis and its associated complications.

Keywords

Ox-LDL receptors / atherosclerosis / foam cell

References

[1] Teo KK, Rafiq T. Cardiovascular risk factors and prevention: a perspective from developing countries. Can J Cardiol. 2021;37(5):733–743. doi: 10.1016/j.cjca.2021.02.009

[2] Teo K.K., Rafiq T. Cardiovascular risk factors and prevention: a perspective from developing countries // Can J Cardiol. 2021. Vol. 37, N 5. P. 733–743. doi: 10.1016/j.cjca.2021.02.009

[3] Gordon DJ, Knoke J, Probstfield JL, et al. High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the lipid research clinics coronary primary prevention trial. Circulation. 1986;74(6):1217–1225. doi: 10.1161/01.cir.74.6.1217

[4] Gordon D.J., Knoke J., Probstfield J.L., et al. High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the lipid research clinics coronary primary prevention trial // Circulation. 1986. Vol. 74, N 6. P. 1217–1225. doi: 10.1161/01.cir.74.6.1217

[5] Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Münster study. Am J Cardiol. 1992;70(7):733–737. doi: 10.1016/0002-9149(92)90550-i

[6] Assmann G., Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Münster study // Am J Cardiol. 1992. Vol. 70, N 7. P. 733–737. doi: 10.1016/0002-9149(92)90550-i

[7] Gordon DJ, Rifkind BM. High-density lipoprotein — the clinical implications of recent studies. N Engl J Med. 1989;321(19): 1311–1316. doi: 10.1056/NEJM198911093211907

[8] Gordon D.J., Rifkind B.M. High-density lipoprotein — the clinical implications of recent studies // N Engl J Med. 1989. Vol. 321, N 19. P. 1311–1316. doi: 10.1056/NEJM198911093211907

[9] Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. Circulation. 1992;85(1):37–45. doi: 10.1161/01.cir.85.1.37

[10] Manninen V., Tenkanen L., Koskinen P., et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki heart study. Implications for treatment // Circulation. 1992. Vol. 85, N 1. P. 37–45. doi: 10.1161/01.cir.85.1.37

[11] Stampfer MJ, Sacks FM, Salvini S, et al. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med. 1991;325(6):373–381. doi: 10.1056/NEJM199108083250601

[12] Stampfer M.J., Sacks F.M., Salvini S., et al. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction // N Engl J Med. 1991. Vol. 325, N 6. P. 373–381. doi: 10.1056/NEJM199108083250601

[13] Sniderman A, Shapiro S, Marpole D, et al. Association of coronary atherosclerosis with hyperapobetalipoproteinemia [increased protein but normal cholesterol levels in human plasma low density (beta) lipoproteins]. Proc Natl Acad Sci U S A. 1980;77(1):604–608. doi: 10.1073/pnas.77.1.604

[14] Sniderman A., Shapiro S., Marpole D., et al. Association of coronary atherosclerosis with hyperapobetalipoproteinemia [increased protein but normal cholesterol levels in human plasma low density (beta) lipoproteins] // Proc Natl Acad Sci USA. 1980. Vol. 77, N 1. P. 604–608. doi: 10.1073/pnas.77.1.604

[15] Lu Y, Cui X, Zhang L, et al. The functional role of lipoproteins in atherosclerosis: novel directions for diagnosis and targeting therapy. Aging Dis. 2022;13(2):491–520. doi: 10.14336/AD.2021.0929

[16] Lu Y., Cui X., Zhang L., et al. The functional role of lipoproteins in atherosclerosis: novel directions for diagnosis and targeting therapy // Aging Dis. 2022. Vol. 13, N 2. P. 491–520. doi: 10.14336/AD.2021.0929

[17] Luchetti F, Crinelli R, Nasoni MG, et al. LDL receptors, caveolae and cholesterol in endothelial dysfunction: oxLDLs accomplices or victims? Br J Pharmacol. 2021;178(16):3104–3114. doi: 10.1111/bph.15272

[18] Luchetti F., Crinelli R., Nasoni M.G., et al. LDL receptors, caveolae and cholesterol in endothelial dysfunction: oxLDLs accomplices or victims? // Br J Pharmacol. 2021. Vol. 178, N 16. P. 3104–3114. doi: 10.1111/bph.15272

[19] Levitan I, Volkov S, Subbaiah PV. Oxidized LDL: diversity, patterns of recognition, and pathophysiology. Antioxid Redox Signal. 2010;13(1):39–75. doi: 10.1089/ars.2009.2733

[20] Levitan I., Volkov S., Subbaiah P.V. Oxidized LDL: diversity, patterns of recognition, and pathophysiology // Antioxid Redox Signal. 2010. Vol. 13, N 1. P. 39–75. doi: 10.1089/ars.2009.2733

[21] Parthasarathy S, Raghavamenon A, Garelnabi MO, Santanam N. Oxidized low-density lipoprotein. Methods Mol Biol. 2010;610: 403–417. doi: 10.1007/978-1-60327-029-8_24

[22] Parthasarathy S., Raghavamenon A., Garelnabi M.O., Santanam N. Oxidized low-density lipoprotein // Methods Mol Biol. 2010. Vol. 610. P. 403–417. doi: 10.1007/978-1-60327-029-8_24

[23] Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29(4):431–438. doi: 10.1161/ATVBAHA.108.179564

[24] Goldstein J.L., Brown M.S. The LDL receptor // Arterioscler Thromb Vasc Biol. 2009. Vol. 29, N 4. P. 431–438. doi: 10.1161/ATVBAHA.108.179564

[25] Zhang Y, Ma KL, Ruan XZ, Liu BC. Dysregulation of the low-density lipoprotein receptor pathway is involved in lipid disorder-mediated organ injury. Int J Biol Sci. 2016;12(5):569–579. doi: 10.7150/ijbs.14027

[26] Zhang Y., Ma K.L., Ruan X.Z., Liu B.C. Dysregulation of the low-density lipoprotein receptor pathway is involved in lipid disorder-mediated organ injury // Int J Biol Sci. 2016. Vol. 12, N 5. P. 569–579. doi: 10.7150/ijbs.14027

[27] Yoshida H, Kisugi R. Mechanisms of LDL oxidation. Clin Chim Acta. 2010;411(23–24):1875–1882. doi: 10.1016/j.cca.2010.08.038

[28] Yoshida H., Kisugi R. Mechanisms of LDL oxidation // Clin Chim Acta. 2010. Vol. 411, N 23–24. P. 1875–1882. doi: 10.1016/j.cca.2010.08.038

[29] Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol. 2006;26(8): 1702–1711. doi: 10.1161/01.ATV.0000229218.97976.43

[30] Moore K.J., Freeman M.W. Scavenger receptors in atherosclerosis: beyond lipid uptake // Arterioscler Thromb Vasc Biol. 2006. Vol. 26, N 8. P. 1702–1711. doi: 10.1161/01.ATV.0000229218.97976.43

[31] Alquraini A, El Khoury J. Scavenger receptors. Curr Biol. 2020;30(14):R790–R795. doi: 10.1016/j.cub.2020.05.051

[32] Alquraini A., El Khoury J. Scavenger receptors // Curr Biol. 2020. Vol. 30, N 14. P. R790–R795. doi: 10.1016/j.cub.2020.05.051

[33] Chistiakov DA, Melnichenko AA, Myasoedova VA, et al. Mechanisms of foam cell formation in atherosclerosis. J Mol Med (Berl). 2017;95(11):1153–1165. doi: 10.1007/s00109-017-1575-8

[34] Chistiakov D.A., Melnichenko A.A., Myasoedova VA, et al. Mechanisms of foam cell formation in atherosclerosis // J Mol Med (Berl). 2017. Vol. 95, N 11. P. 1153–1165. doi: 10.1007/s00109-017-1575-8

[35] Zingg JM, Ricciarelli R, Azzi A. Scavenger receptors and modified lipoproteins: fatal attractions? IUBMB Life. 2000;49(5):397–403. doi: 10.1080/152165400410245

[36] Zingg J.M., Ricciarelli R., Azzi A. Scavenger receptors and modified lipoproteins: fatal attractions? // IUBMB Life. 2000. Vol. 49, N 5. P. 397–403. doi: 10.1080/152165400410245

[37] Hartley A, Haskard D, Khamis R. Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis — Novel insights and future directions in diagnosis and therapy. Trends Cardiovasc Med. 2019;29(1):22–26. doi: 10.1016/j.tcm.2018.05.010

[38] Hartley A., Haskard D., Khamis R. Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis — Novel insights and future directions in diagnosis and therapy // Trends Cardiovasc Med. 2019. Vol. 29, N 1. P. 22–26. doi: 10.1016/j.tcm.2018.05.010

[39] Sukhorukov VN, Karagodin VP, Orekhov AN. Atherogenic modification of low-density lipoproteins. Biomed Khim. 2016;62(4): 391–402. doi: 10.18097/PBMC20166204391

[40] Sukhorukov V.N., Karagodin V.P., Orekhov A.N. Atherogenic modification of low-density lipoproteins // Biomed Khim. 2016. Vol. 62, N 4. P. 391–402. doi: 10.18097/PBMC20166204391

[41] Maiolino G, Rossitto G, Caielli P, et al. The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. Mediators Inflamm. 2013;2013:714653. doi: 10.1155/2013/714653

[42] Maiolino G., Rossitto G., Caielli P., et al. The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts // Mediators Inflamm. 2013. Vol. 2013. P. 714653. doi: 10.1155/2013/714653

[43] Nour Eldin EE, Almarzouki A, Assiri AM, et al. Oxidized low density lipoprotein and total antioxidant capacity in type-2 diabetic and impaired glucose tolerance Saudi men. Diabetol Metab Syndr. 2014;6(1):94. doi: 10.1186/1758-5996-6-94

[44] Nour Eldin E.E., Almarzouki A., Assiri A.M., et al. Oxidized low density lipoprotein and total antioxidant capacity in type-2 diabetic and impaired glucose tolerance Saudi men // Diabetol Metab Syndr. 2014. Vol. 6, N 1. P. 94. doi: 10.1186/1758-5996-6-94

[45] Gimbrone MA Jr, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 2016;118(4): 620–636. doi: 10.1161/CIRCRESAHA.115.306301

[46] Gimbrone M.A. Jr, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis // Circ Res. 2016. Vol. 118, N 4. P. 620–636. doi: 10.1161/CIRCRESAHA.115.306301

[47] Behbodikhah J, Ahmed S, Elyasi A, et al. Apolipoprotein B and cardiovascular disease: biomarker and potential therapeutic target. Metabolites. 2021;11(10):690. doi: 10.3390/metabo11100690

[48] Behbodikhah J., Ahmed S., Elyasi A., et al. Apolipoprotein B and cardiovascular disease: biomarker and potential therapeutic target // Metabolites. 2021. Vol. 11, N 10. P. 690. doi: 10.3390/metabo11100690

[49] Suciu CF, Prete M, Ruscitti P, et al. Oxidized low density lipoproteins: The bridge between atherosclerosis and autoimmunity. Possible implications in accelerated atherosclerosis and for immune intervention in autoimmune rheumatic disorders. Autoimmun Rev. 2018;17(4):366–375. doi: 10.1016/j.autrev.2017.11.028

[50] Suciu C.F., Prete M., Ruscitti P., et al. Oxidized low density lipoproteins: The bridge between atherosclerosis and autoimmunity. Possible implications in accelerated atherosclerosis and for immune intervention in autoimmune rheumatic disorders // Autoimmun Rev. 2018. Vol. 17, N 4. P. 366–375. doi: 10.1016/j.autrev.2017.11.028

[51] Valente AJ, Irimpen AM, Siebenlist U, Chandrasekar B. OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators. Free Radic Biol Med. 2014;70:117–128. doi: 10.1016/j.freeradbiomed.2014.02.014

[52] Valente A.J., Irimpen A.M., Siebenlist U., Chandrasekar B. OxLDL induces endothelial dysfunction and death via TRAF3IP2: inhibition by HDL3 and AMPK activators // Free Radic Biol Med. 2014. Vol. 70. P. 117–128. doi: 10.1016/j.freeradbiomed.2014.02.014

[53] Gradinaru D, Borsa C, Ionescu C, Prada GI. Oxidized LDL and NO synthesis — Biomarkers of endothelial dysfunction and ageing. Mech Ageing Dev. 2015;151:101–113. doi: 10.1016/j.mad.2015.03.003

[54] Gradinaru D., Borsa C., Ionescu C., Prada G.I. Oxidized LDL and NO synthesis — Biomarkers of endothelial dysfunction and ageing // Mech Ageing Dev. 2015. Vol. 151. P. 101–113. doi: 10.1016/j.mad.2015.03.003

[55] Malekmohammad K, Sewell RDE, Rafieian-Kopaei M. Antioxidants and Atherosclerosis: Mechanistic Aspects. Biomolecules. 2019;9(8):301. doi: 10.3390/biom9080301

[56] Malekmohammad K., Sewell R.D.E., Rafieian-Kopaei M. Antioxidants and atherosclerosis: mechanistic aspects // Biomolecules. 2019. Vol. 9, N 8. P. 301. doi: 10.3390/biom9080301

[57] Marchio P, Guerra-Ojeda S, Vila JM, et al. Targeting early atherosclerosis: a focus on oxidative stress and inflammation. Oxid Med Cell Longev. 2019;2019:8563845. doi: 10.1155/2019/8563845

[58] Marchio P., Guerra-Ojeda S., Vila J.M., et al. Targeting early atherosclerosis: a focus on oxidative stress and inflammation // Oxid Med Cell Longev. 2019. Vol. 2019. P. 8563845. doi: 10.1155/2019/8563845

[59] Thankam FG, Rai T, Liu J, et al. Minimally oxidized-LDL-driven alterations in the level of pathological mediators and biological processes in carotid atherosclerosis. Cardiol Cardiovasc Med. 2022;6(2):137–156. doi: 10.26502/fccm.92920251

[60] Thankam F.G., Rai T., Liu J., et al. Minimally oxidized-LDL-driven alterations in the level of pathological mediators and biological processes in carotid atherosclerosis // Cardiol Cardiovasc Med. 2022. Vol. 6, N 2. P. 137–156. doi: 10.26502/fccm.92920251

[61] Tsimikas S, Miller YI. Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. Curr Pharm Des. 2011;17(1):27–37. doi: 10.2174/138161211795049831

[62] Tsimikas S., Miller Y.I. Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease // Curr Pharm Des. 2011. Vol. 17, N 1. P. 27–37. doi: 10.2174/138161211795049831

[63] Itabe H, Obama T. The oxidized lipoproteins in vivo: its diversity and behavior in the human circulation. Int J Mol Sci. 2023;24(6):5747. doi: 10.3390/ijms24065747

[64] Itabe H., Obama T. The oxidized lipoproteins in vivo: its diversity and behavior in the human circulation // Int J Mol Sci. 2023. Vol. 24, N 6. P. 5747. doi: 10.3390/ijms24065747

[65] van den Berg VJ, Vroegindewey MM, Kardys I, et al. Anti-oxidized LDL antibodies and coronary artery disease: a systematic review. Antioxidants (Basel). 2019;8(10):484. doi: 10.3390/antiox8100484

[66] van den Berg V.J., Vroegindewey M.M., Kardys I., et al. Anti-Oxidized LDL Antibodies and coronary artery disease: a systematic review // Antioxidants (Basel). 2019. Vol. 8, N 10. P. 484. doi: 10.3390/antiox8100484

[67] Babakr AT, Elsheikh OM, Almarzouki AA, et al. Relationship between oxidized low-density lipoprotein antibodies and obesity in different glycemic situations. Diabetes Metab Syndr Obes. 2014;7: 513–520. doi: 10.2147/DMSO.S70904

[68] Babakr A.T., Elsheikh O.M., Almarzouki A.A., et al. Relationship between oxidized low-density lipoprotein antibodies and obesity in different glycemic situations // Diabetes Metab Syndr Obes. 2014. Vol. 7. P. 513–520. doi: 10.2147/DMSO.S70904

[69] Ylä-Herttuala S. Is oxidized low-density lipoprotein present in vivo? Curr Opin Lipidol. 1998;9(4):337–344. doi: 10.1097/00041433-199808000-00009

[70] Ylä-Herttuala S. Is oxidized low-density lipoprotein present in vivo? // Curr Opin Lipidol. 1998. Vol. 9, N 4. P. 337–344. doi: 10.1097/00041433-199808000-00009

[71] Nielsen LB. Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis. 1999;143(2):229–243. doi: 10.1016/s0021-9150(99)00064-7

[72] Nielsen L.B. Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux // Atherosclerosis. 1999. Vol. 143, N 2. P. 229–243. doi: 10.1016/s0021-9150(99)00064-7

[73] Pirillo A, Norata GD, Catapano AL. LOX-1, OxLDL, and atherosclerosis. Mediators Inflamm. 2013;2013:152786. doi: 10.1155/2013/152786

[74] Pirillo A., Norata G.D., Catapano A.L. LOX-1, OxLDL, and atherosclerosis // Mediators Inflamm. 2013. Vol. 2013. P. 152786. doi: 10.1155/2013/152786

[75] Knaus UG. Oxidants in physiological processes. Handb Exp Pharmacol. 2021;264:27–47. doi: 10.1007/164_2020_380

[76] Knaus U.G. Oxidants in physiological processes // Handb Exp Pharmacol. 2021. Vol. 264. P. 27–47. doi: 10.1007/164_2020_380

[77] Frangie C, Daher J. Role of myeloperoxidase in inflammation and atherosclerosis (Review). Biomed Rep. 2022;16(6):53. doi: 10.3892/br.2022.1536

[78] Frangie C., Daher J. Role of myeloperoxidase in inflammation and atherosclerosis (Review) // Biomed Rep. 2022. Vol. 16, N 6. P. 53. doi: 10.3892/br.2022.1536

[79] Jomova K, Makova M, Alomar SY, et al. Essential metals in health and disease. Chem Biol Interact. 2022;367:110173. doi: 10.1016/j.cbi.2022.110173

[80] Jomova K., Makova M., Alomar S.Y., et al. Essential metals in health and disease // Chem Biol Interact. 2022. Vol. 367. P. 110173. doi: 10.1016/j.cbi.2022.110173

[81] Shang D, Liu H, Tu Z. Pro-inflammatory cytokines mediating senescence of vascular endothelial cells in atherosclerosis. Fundam Clin Pharmacol. 2023;37(5):928–936. doi: 10.1111/fcp.12915

[82] Shang D., Liu H., Tu Z. Pro-inflammatory cytokines mediating senescence of vascular endothelial cells in atherosclerosis // Fundam Clin Pharmacol. 2023. Vol. 37, N 5. P. 928–936. doi: 10.1111/fcp.12915

[83] Meng Z, Yan C, Deng Q, et al. Oxidized low-density lipoprotein induces inflammatory responses in cultured human mast cells via Toll-like receptor 4. Cell Physiol Biochem. 2013;31(6):842–853. doi: 10.1159/000350102

[84] Meng Z., Yan C., Deng Q., et al. Oxidized low-density lipoprotein induces inflammatory responses in cultured human mast cells via Toll-like receptor 4 // Cell Physiol Biochem. 2013. Vol. 31, N 6. P. 842–853. doi: 10.1159/000350102

[85] Khan MA, Mohammad I, Banerjee S, et al. Oxidized LDL receptors: a recent update. Curr Opin Lipidol. 2023;34(4):147–155. doi: 10.1097/MOL.0000000000000884

[86] Khan M.A., Mohammad I., Banerjee S., et al. Oxidized LDL receptors: a recent update // Curr Opin Lipidol. 2023. Vol. 34, N 4. P. 147–155. doi: 10.1097/MOL.0000000000000884

[87] Babakr A.T. Scavenger receptors: different classes and their role in the uptake of oxidized low-density lipoproteins. Biomed Pharmacol J. 2024;17(2). doi: 10.13005/bpj/2897

[88] Babakr A.T. Scavenger receptors: different classes and their role in the uptake of oxidized low-density lipoproteins // Biomed Pharmacol J. 2024. Vol. 17, N 2. doi: 10.13005/bpj/2897

[89] PrabhuDas MR, Baldwin CL, Bollyky PL, et al. A consensus definitive classification of scavenger receptors and their roles in health and disease. J Immunol. 2017;198(10):3775–3789. doi: 10.4049/jimmunol.1700373

[90] PrabhuDas M.R., Baldwin C.L., Bollyky P.L., et al. A consensus definitive classification of scavenger receptors and their roles in health and disease // J Immunol. 2017. Vol. 198, N 10. P. 3775–3789. doi: 10.4049/jimmunol.1700373

[91] Stephen SL, Freestone K, Dunn S, et al. Scavenger receptors and their potential as therapeutic targets in the treatment of cardiovascular disease. Int J Hypertens. 2010;2010:646929. doi: 10.4061/2010/646929

[92] Stephen S.L., Freestone K., Dunn S., et al. Scavenger receptors and their potential as therapeutic targets in the treatment of cardiovascular disease // Int J Hypertens. 2010. Vol. 2010. P. 646929. doi: 10.4061/2010/646929

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