[Frontiers In Bioscience, Landmark, 23, 1422-1444, March 1, 2018]

Modified lipoproteins as biomarkers of atherosclerosis

Alexander N. Orekhov1,2, Igor A. Sobenin3

1Institute for Atherosclerosis Research, Skolkovo Innovative Center, Russian Federation, 143025 Moscow, Russia, 2Institute of General Pathology and Pathophysiology, Russian Federation, 125315 Moscow, Russia, 3Russian Cardiology Research and Production Complex, Moscow, Russian Federation, 125315 Moscow, Russia


1. Abstract
2. Introduction
2.1. The paradigm of lipid theory of atherogenesis and the value of low density lipoprotein and high density lipoprotein as risk factors
2.2. The role of modified LDL in atherosclerosis
2.3. Evaluation of LDL and HDL as risk factors: AHA recommendations
3. High density lipoprotein in atherogenesis
3.1. Epidemiological data demonstrating negative association of HDL with atherosclerotic disease
3.2. Possible mechanisms of anti-atherogenic effects of HDL
3.3. Unsuccessful attempts to use HDL increase against atherosclerosis
3.4. Evaluation of the emerging potential biomarkers
4. Modified ldl in atherogenesis
4.1. Oxidized LDL: myth or reality?
4.2. Known modified LDL types present in vivo
4.3. Mechanisms of modified LDL-induced atherogenesis
4.4. Probing for the role of modified LDL in atherosclerosis: in vitro and clinical studies
5. Studies of desialylated LDL
6. Conclusion
7. Acknowledgement
8. References


Pathogenesis of atherosclerosis and the search for novel therapies and diagnostic markers remain major problems of modern medicine. Currently available therapeutic approaches are often not sufficiently effective, probably due to the complexity of the disease mechanisms. This review focuses on the evaluation of low density lipoprotein (LDL) and high density lipoprotein (HDL) as risk factors of atherosclerosis. We summarize the current paradigm of LDL involvement in atherogenesis and HDL presumably protective properties. We next discuss the available evidence for the protective effect of HDL and the consequences of HDL dysfunction. Finally, we question the currently widely accepted hypothesis of the central role of oxidized LDL in atherogenesis and present an alternative concept of multiple modification of LDL that confers its pro-atherogenic properties.


1. J Frohlich, A Al-Sarraf: Cardiovascular risk and atherosclerosis prevention. Cardiovasc Pathol 22, 16-18 (2013)
DOI: 10.1016/j.carpath.2012.03.001

2. M Viola, E Karousou, ML D’Angelo, P Moretto, I Caon, G Luca, A Passi, D Vigetti: Extracellular matrix in atherosclerosis: hyaluronan and proteoglycans insights. Curr Med Chem 23, 2958-2971 (2016)
DOI: 10.2174/0929867323666160607104602

3. J Plakkal Ayyappan, A Paul, YH Goo: Lipid droplet-associated proteins in atherosclerosis. Mol Med Rep 13, 4527-4534 (2016)
DOI: 10.3892/mmr.2016.5099

4. C Bancells, S Benítez, M Jauhiainen, J Ordóñez-Llanos, PT Kovanen, S Villegas, JL Sánchez-Quesada, K Oörni: High binding affinity of electronegative LDL to human aortic proteoglycans depends on its aggregation level. J Lipid Res 50, 446-455 (2009)
DOI: 10.1194/jlr.M800318-JLR200

5. JA Dubland, GA Francis: So Much Cholesterol: the unrecognized importance of smooth muscle cells in atherosclerotic foam cell formation. Curr Opin Lipidol 27, 155-161 (2016)
DOI: 10.1097/MOL.0000000000000279

6. XH Yu, YC Fu, DW Zhang, K Yin, CK Tang: Foam cells in atherosclerosis. Clin Chim Acta 424, 245-252 (2013)
DOI: 10.1016/j.cca.2013.06.006

7. Y Yuan, P Li, J Ye: Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis. Protein Cell 3, 173-181 (2012)
DOI: 10.1007/s13238-012-2025-6

8. RM Krauss: Lipoprotein subfractions and cardiovascular disease risk. Curr Opin Lipidol 21, 305-311 (2010)
DOI: 10.1097/MOL.0b013e32833b7756

9. E Favari, A Chroni, UJ Tietge, I Zanotti, JC Escolà-Gil, F Bernini: Cholesterol efflux and reverse cholesterol transport. Handb Exp Pharmacol 224, 181-206 (2015)
DOI: 10.1007/978-3-319-09665-0_4

10. AN Orekhov, VV Tertov, DN Mukhin, VE Koteliansky, MA Glukhova, MG Frid, GK Sukhova, KhA Khashimov, VN Smirnov: Insolubilization of low density lipoprotein induces cholesterol accumulation in cultured subendothelial cells of human aorta. Atherosclerosis 79, 59-70 (1989)
DOI: 10.1016/0021-9150(89)90034-8

11. VV Tertov, VV Kaplun, IA Sobenin, AN Orekhov: Low-density lipoprotein modification occurring in human plasma possible mechanism of in vivo lipoprotein desialylation as a primary step of atherogenic modification. Atherosclerosis 138, 183-195 (1998)
DOI: 10.1016/S0021-9150(98)00023-9

12. P Avogaro, GB Bon, G Cazzolato: Presence of a modified low density lipoprotein in humans. Arteriosclerosis 8, 79-87 (1988)
DOI: 10.1161/01.ATV.8.1.79

13. AN Orekhov, YV Bobryshev, IA Sobenin, AA Melnichenko, DA Chistiakov: Modified low density lipoprotein and lipoprotein-containing circulating immune complexes as diagnostic and prognostic biomarkers of atherosclerosis and type 1 diabetes macrovascular disease. Int J Mol Sci 15, 12807-12841 (2014)
DOI: 10.3390/ijms150712807

14. EA Ivanova, YV Bobryshev, AN Orekhov: LDL electronegativity index: a potential novel index for predicting cardiovascular disease. Vasc Health Risk Manag 11, 525-532 (2015)

15. JS Monette, PM Hutchins, GE Ronsein, J Wimberger, AD Irwin, C Tang, JD Sara, B Shao, T Vaisar, A Lerman, JW Heinecke: Patients with coronary endothelial dysfunction have impaired cholesterol efflux capacity and reduced HDL particle concentration. Circ Res 119, 83-90 (2016)
DOI: 10.1161/CIRCRESAHA.116.308357

16. M Ogura, M Hori, M Harada-Shiba: Association between cholesterol efflux capacity and atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia. Artherioscler Thromb Vasc Biol 36, 181-188 (2016)

17. DJ Brotman, E Walker, MS Lauer, RG O’Brien: In search of fewer independent risk factors. Arch Intern Med 165, 138-145 (2005)
DOI: 10.1001/archinte.165.2.138

18. NJ Stone, JG Robinson, AH Lichtenstein, CN Bairey Merz, CB Blum, RH Eckel, AC Goldberg, D Gordon, D Levy, DM Lloyd-Jones, P McBride, JS Schwartz, ST Shero, SC Smith Jr., K Watson, PW Wilson, KM Eddleman, NM Jarrett, K LaBresh, L Nevo, J Wnek, JL Anderson, JL Halperin, NM Albert, B Bozkurt, RG Brindis, LH Curtis, D DeMets, JS Hochman, RJ Kovacs, EM Ohman, SJ Pressler, FW Sellke, WK Shen, SC Smith Jr., GF Tomaselli: American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129, S1-45 (2014)
DOI: 10.1161/01.cir.0000437738.63853.7a

19. Authors/Task Force Members: AL Catapano, I Graham, G De Backer, O Wiklund, MJ Chapman, H Drexel, AW Hoes, CS Jennings, U Landmesser, TR Pedersen, Z Reiner, G Riccardi, MR Taskinen, L Tokgozoglu, WM Verschuren, C Vlachopoulos, DA Wood, JL Zamorano: 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 37, 2999-3058 (2016)

20. IM Graham, AL Catapano, ND Wong: Current guidelines on prevention with a focus on dyslipidemias. Cardiovasc Diagn Ther 7, S4-S10 (2017)
DOI: 10.21037/cdt.2017.04.04

21. FM Piepoli: 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Int J Behav Med 24, 321-419 (2017)
DOI: 10.1007/s12529-016-9583-6

22. AJ Kooter, PJ Kostense, J Groenewold, A Thijs, N Sattar, YM Smulders: Integrating information from novel risk factors with calculated risks: the critical impact of risk factor prevalence. Circulation 124, 741-745 (2011)
DOI: 10.1161/CIRCULATIONAHA.111.035725

23. JP Ioannidis, I Tzoulaki: Minimal and null predictive effects for the most popular blood biomarkers of cardiovascular disease. Circ Res 110, 658-662 (2012)
DOI: 10.1161/RES.0b013e31824da8ad

24. LG Gilstrap, TJ Wang: Biomarkers and cardiovascular risk assessment for primary prevention: an update. Clin Chem 58, 72–82 (2012)
DOI: 10.1373/clinchem.2011.165712

25. I Tzoulaki, KC Siontis, E Evangelou, JP Ioannidis: Bias in associations of emerging biomarkers with cardiovascular disease. JAMA Intern Med 173, 664-671 (2013)
DOI: 10.1001/jamainternmed.2013.3018

26. T Gordon, WP Castelli, MC Hjortland, WB Kannel, TR Dawber: High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 62, 707–714 (1977)
DOI: 10.1016/0002-9343(77)90874-9

27. JJ Genest, JR McNamara, DN Salem, EJ Schaefer: Prevalence of risk factors in men with premature coronary artery disease. Am J Cardiol 67, 1185–1189 (1991)
DOI: 10.1016/0002-9149(91)90924-A

28. Emerging Risk Factors Collaboration, E Di Angelantonio, N Sarwar, P Perry, S Kaptoge, KK Ray, A Thompson, AM Wood, S Lewington, N Sattar, CJ Packard, R Collins, SG Thompson, J Danesh: Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009)
DOI: 10.1001/jama.2009.1619

29. WA van der Steeg, I Holme, SM Boekholdt, ML Larsen, C Lindahl, ES Stroes, MJ Tikkanen, NJ Wareham, O Faergeman, AG Olsson, TR Pedersen, KT Khaw, JJ Kastelein: High- density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: signi cance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol 51, 634–642 (2008)
DOI: 10.1016/j.jacc.2007.09.060

30. B Bowe, Y Xie, H Xian, S Balasubramanian, MA Zayed, Z Al-Aly: High density lipoprotein cholesterol and the risk of all-cause mortality among U.S. veterans. Clin J Am Soc Nephrol 11, 1784-1793 (2016)
DOI: 10.2215/CJN.00730116

31. J Bartlett, IM Predazzi, SM Williams, WS Bush, Y Kim, S Havas, PP Toth, S Fazio, M Miller: Is isolated low high-density lipoprotein cholesterol a cardiovascular disease risk factor? New insights from the Framingham offspring study. Circ Cardiovasc Qual Outcomes 9, 206–212 (2016)
DOI: 10.1161/CIRCOUTCOMES.115.002436

32. W März, ME Kleber, H Scharnagl, T Speer, S Zewinger, A Ritsch, KG Parhofer, A von Eckardstein, U Landmesser, U Laufs: HDL cholesterol: reappraisal of its clinical relevance. Clin Res Cardiol (2017) Mar 24. doi: 10.1.007/s00392-017-1106-1 (Epub ahead of print)
DOI: 10.1.007/s00392-017-1106-1

33. R Frikke-Schmidt, BG Nordestgaard, P Schnohr, R Steffensen, A Tybjaerg-Hansen: Mutation in ABCA1 predicted risk of ischemic heart disease in the Copenhagen City Heart Study Population. J Am Coll Cardiol 46, 1516–1520 (2005)
DOI: 10.1016/j.jacc.2005.06.066

34. RD Santos, BF Asztalos, LR Martinez, MH Miname, E Polisecki, EJ Schaefer: Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states. J Clin Lipidol 2, 237–247 (2008)
DOI: 10.1016/j.jacl.2008.06.002

35. R Frikke-Schmidt, BG Nordestgaard, GB Jensen, R Steffensen, A Tybjaerg-Hansen: Genetic variation in ABCA1 predicts ischemic heart disease in the general population. Arterioscler Thromb Vasc Biol 28, 180–186 (2008)
DOI: 10.1161/ATVBAHA.107.153858

36. AE Bochem, DF van Wijk, AG Holleboom, R Duivenvoorden, MM Motazacker, GM Dallinga-Thie, E de Groot, JJ Kastelein, AJ Nederveen, GK Hovingh, ES Stroes: ABCA1 mutation car- riers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden. Eur Heart J 34, 286–291 (2013)
DOI: 10.1093/eurheartj/ehs376

37. R Frikke-Schmidt, BG Nordestgaard, MC Stene, AA Sethi, AT Remaley, P Schnohr, P Grande, A Tybjaerg-Hansen: Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 299, 2524-2532 (2008)
DOI: 10.1001/jama.299.21.2524

38. TH Johannsen, PR Kamstrup, RV Andersen, GB Jensen, H Sillesen, A Tybjaerg-Hansen, BG Nordestgaard: Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease. J Clin Endocrinol Metab 94, 1264-1273 (2009)
DOI: 10.1210/jc.2008-1342

39. CL Haase, A Tybjaerg-Hansen, P Grande, R Frikke-Schmidt: Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J Clin Endocrinol Metab 95, E500–10 (2010)
DOI: 10.1210/jc.2010-0450

40. BF Voight, GM Peloso, M Orho-Melander, R Frikke-Schmidt, M Barbalic, MK Jensen, G Hindy, H Holm, EL Ding, T Johnson, H Schunkert, NJ Samani, R Clarke, JC Hopewell, JF Thompson, M Li, G Thorleifsson, C Newton-Cheh, K Musunuru, JP Pirruccello, D Saleheen, L Chen, A Stewart, A Schillert, U Thorsteinsdottir, G Thorgeirsson, S Anand, JC Engert, T Morgan, J Spertus, M Stoll, K Berger, N Martinelli, D Girelli, PP McKeown, CC Patterson, SE Epstein, J Devaney, MS Burnett, V Mooser, S Ripatti, I Surakka, MS Nieminen, J Sinisalo, ML Lokki, M Perola, A Havulinna, U de Faire, B Gigante, E Ingelsson, T Zeller, P Wild, PI de Bakker, OH Klungel, AH Maitland-van der Zee, BJ Peters, A de Boer, DE Grobbee, PW Kamphuisen, VH Deneer, CC Elbers, NC Onland-Moret, MH Hofker, C Wijmenga, WM Verschuren, JM Boer, YT van der Schouw, A Rasheed, P Frossard, S Demissie, C Willer, R Do, JM Ordovas, GR Abecasis, M Boehnke, KL Mohlke, MJ Daly, C Guiducci, NP Burtt, A Surti, E Gonzalez, S Purcell, S Gabriel, J Marrugat, J Peden, J Erdmann, P Diemert, C Willenborg, IR König, M Fischer, C Hengstenberg, A Ziegler, I Buysschaert, D Lambrechts, F Van de Werf, KA Fox, NE El Mokhtari, D Rubin, J Schrezenmeir, S Schreiber, A Schäfer, J Danesh, S Blankenberg, R Roberts, R McPherson, H Watkins, AS Hall, K Overvad, E Rimm, E Boerwinkle, A Tybjaerg-Hansen, LA Cupples, MP Reilly, O Melander, PM Mannucci, D Ardissino, D Siscovick, R Elosua, K Stefansson, CJ O’Donnell, V Salomaa, DJ Rader, L Peltonen, SM Schwartz, D Altshuler, S Kathiresan: Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380, 572–580 (2012)
DOI: 10.1016/S0140-6736(12)60312-2

41. CL Haase, A Tybjaerg-Hansen, AA Qayyum, J Schou, BG Nordestgaard, R Frikke-Schmidt: LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab 97, E248–256 (2012)
DOI: 10.1210/jc.2011-1846

42. R Do, CJ Willer, EM Schmidt, S Sengupta, C Gao, GM Peloso, S Gustafsson, S Kanoni, A Ganna, J Chen, ML Buchkovich, S Mora, JS Beckmann, JL Bragg-Gresham, HY Chang, A Demirkan, HM Den Hertog, LA Donnelly,GB Ehret, T Esko, MF Feitosa, T Ferreira, K Fischer, P Fontanillas, RM Fraser, DF Freitag, D Gurdasani, K Heikkilä, E Hyppönen, A Isaacs, AU Jackson, A Johansson, T Johnson, M Kaakinen, J Kettunen, ME Kleber, X Li, J Luan, LP Lyytikäinen, PK Magnusson, M Mangino, E Mihailov, ME Montasser, M Müller-Nurasyid, IM Nolte, JR O’Connell, CD Palmer, M Perola, AK Petersen, S Sanna, R Saxena, SK Service, S Shah, S Sungin, C Sidore, C Song, RJ Strawbridge, I Surakka, T Tanaka, TM Teslovich, G Thorleifsson, EG Van den Herik, BF Voight, KA Volcik, LL Waite, A Wong, Y Wu, W Zhang, D Absher, G Asiki, I Barroso, LF Been, JL Bolton, LL Bonnycastle, P Brambilla, MS Burnett, G Cesana, M Dimitriou, AS Doney, A Döring, P Elliott, SE Epstein, GI Eyjolfsson, B Gigante, MO Goodarzi, H Grallert, ML Gravito, CJ Groves, G Hallmans, AL Hartikainen, C Hayward, D Hernandez, AA Hicks, H Holm, YJ Hung, T Illig, MR Jones, P Kaleebu, JJ Kastelein, KT Khaw, E Kim, N Klopp, P Komulainen, M Kumari, C Langenberg, T Lehtimäki, SY Lin, J Lindström, RJ Loos, F Mach, WL Mc Ardle, C Meisinger, BD Mitchell, G Müller, R Nagaraja, N Narisu, TV Nieminen, RN Nsubuga, I Olafsson, KK Ong, A Palotie, T Papamarkou, C Pomilla, A Pouta, DJ Rader, MP Reilly, PM Ridker, F Rivadeneira, I Rudan, A Ruokonen, N Samani, H Scharnagl, J Seeley, K Silander, A Stancáková, K Stirrups, AJ Swift, L Tiret, AG Uitterlinden, LJ van Pelt, S Vedantam, N Wainwright, C Wijmenga, SH Wild, G Willemsen, T Wilsgaard, JF Wilson, EH Young, JH Zhao, LS Adair, D Arveiler, TL Assimes, S Bandinelli, F Bennett, M Bochud, BO Boehm, DI Boomsma, IB Borecki, SR Bornstein, P Bovet, M Burnier, H Campbell, A Chakravarti, JC Chambers, YD Chen, FS Collins, RS Cooper, J Danesh, G Dedoussis, U de Faire, AB Feranil, J Ferrières, L Ferrucci, NB Freimer, C Gieger, LC Groop, V Gudnason, U Gyllensten, A Hamsten, TB Harris, A Hingorani, JN Hirschhorn, A Hofman, GK Hovingh, CA Hsiung, SE Humphries, SC Hunt, K Hveem, C Iribarren, MR Järvelin, A Jula, M Kähönen, J Kaprio, A Kesäniemi, M Kivimaki, JS Kooner, PJ Koudstaal, RM Krauss, D Kuh, J Kuusisto, KO Kyvik, M Laakso, TA Lakka, L Lind, CM Lindgren, NG Martin, W März, MI McCarthy, CA McKenzie, P Meneton, A Metspalu, L Moilanen, AD Morris, PB Munroe, I Njølstad, NL Pedersen, C Power, PP Pramstaller, JF Price, BM Psaty, T Quertermous, R Rauramaa, D Saleheen, V Salomaa, DK Sanghera, J Saramies, PE Schwarz, WH Sheu, AR Shuldiner, A Siegbahn, TD Spector, K Stefansson, DP Strachan, BO Tayo, E Tremoli, J Tuomilehto, M Uusitupa, CM van Duijn, P Vollenweider, L Wallentin, NJ Wareham, JB Whitfield, BH Wolffenbuttel, D Altshuler, JM Ordovas, E Boerwinkle, CN Palmer, U Thorsteinsdottir, DI Chasman, JI Rotter, PW Franks, S Ripatti, LA Cupples, MS Sandhu, SS Rich, M Boehnke, P Deloukas, KL Mohlke, E Ingelsson, GR Abecasis, MJ Daly, BM Neale, S Kathiresan: Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 45, 1345-1352 (2013)
DOI: 10.1038/ng.2795

43. MV Holmes, FW Asselbergs, TM Palmer, F Drenos, MB Lanktree, CP Nelson, CE Dale, S Padmanabhan, C Finan, DI Swerdlow, V Tragante, EP van Iperen, S Sivapalaratnam, S Shah, CC Elbers, T Shah, J Engmann, C Giambartolomei, J White, D Zabaneh, R Sofat, S McLachlan, UCLEB consortium, PA Doevendans, AJ Balmforth, AS Hall, KE North, B Almoguera, RC Hoogeveen, M Cushman, M Fornage, SR Patel, S Redline, DS Siscovick, MY Tsai, KJ Karczewski, MH Hofker, WM Verschuren, ML Bots, YT van der Schouw, O Melander, AF Dominiczak, R Morris, Y Ben-Shlomo, J Price, M Kumari, J Baumert, A Peters, B Thorand, W Koenig, TR Gaunt, SE Humphries, R Clarke, H Watkins, M Farrall, JG Wilson, SS Rich, PI de Bakker, LA Lange, G Davey Smith, AP Reiner, PJ Talmud, M Kivimäki, DA Lawlor, F Dudbridge, NJ Samani, BJ Keating, AD Hingorani, JP Casas: Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 36, 539–550 (2015)
DOI: 10.1093/eurheartj/eht571

44. A Helgadottir, S Gretarsdottir, G Thorleifsson, E Hjartarson, A Sigurdsson, A Magnusdottir, A Jonasdottir, H Kristjansson, P Sulem, A Oddsson, G Sveinbjornsson, V Steinthorsdottir, T Rafnar, G Masson, I Jonsdottir, I Olafsson, GI Eyjolfsson, O Sigurdardottir, MS Daneshpour, D Khalili, F Azizi, DW Swinkels, L Kiemeney, AA Quyyumi, AI Levey, RS Patel, SS Hayek, IJ Gudmundsdottir, G Thorgeirsson, U Thorsteinsdottir, DF Gudbjartsson, H Holm, K Stefansson: Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat Genet 48, 634–639 (2016)
DOI: 10.1038/ng.3561

45. LR Brunham: HDL as a Causal Factor in Atherosclerosis: Insights from Human Genetics. Curr Atheroscler Rep 18, 71 (2016)
DOI: 10.1007/s11883-016-0623-0

46. JA Glomset: The plasma lecithins: cholesterol acyltransferase reaction. J Lipid Res 9, 155-167 (1968)

47. L Camont, MJ Chapman, A Kontush: Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med 17, 594-603 (2011)
DOI: 10.1016/j.molmed.2011.05.013

48. C Mineo, PW Shaul: Novel biological functions of high-density lipoprotein cholesterol. Circ Res 111, 1079-1090 (2012)
DOI: 10.1161/CIRCRESAHA.111.258673

49. W Annema, A von Eckardstein, PT Kovanen: HDL and atherothrombotic vascular disease. Handb Exp Pharmacol 224, 369-403 (2015)
DOI: 10.1007/978-3-319-09665-0_11

50. MC Phillips: Molecular mechanisms of cellular cholesterol efflux. J Biol Chem 289, 24020-24029 (2014)
DOI: 10.1074/jbc.R114.583658

51. N Wang, D Lan, W Chen, F Matsuura, AR Tall: ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci U S A 101, 9774–9779 (2004)
DOI: 10.1073/pnas.0403506101

52. S Larrede, CM Quinn, W Jessup, E Frisdal, M Olivier, V Hsieh, MJ Kim, EM Van, P Couvert, A Carrie, P Giral, MJ Chapman, M Guerin, GW Le: Stimulation of cholesterol efflux by LXR agonists in cholesterol-loaded human macrophages is ABCA1-dependent but ABCG1-independent. Arterioscler Thromb Vasc Biol 29, 1930-1936 (2009)
DOI: 10.1161/ATVBAHA.109.194548

53. EJ Tarling, PA Edwards: ATP binding cassette transporter G1 (ABCG1) is an intra- cellular sterol transporter. Proc Natl Acad Sci U S A 108, 19719-19724 (2011)
DOI: 10.1073/pnas.1113021108

54. Y Liu, C Tang: Regulation of ABCA1 functions by signaling pathways. Biochim Biophys Acta 1821, 522-529 (2012)
DOI: 10.1016/j.bbalip.2011.08.015

55. DL Michell, KC Vickers: Lipoprotein carriers of microRNAs. Biochim Biophys Acta 1861(12 Pt B):2069-2074 (2016)
DOI: 10.1016/j.bbalip.2016.01.011

56. KC Vickers, BT Palmisano, BM Shoucri, RD Shamburek, AT Remaley: MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol 13, 423-433 (2011)
DOI: 10.1038/ncb2210

57. DG Rader, GK Hovingh: HDL and cardiovascular disease. Lancet 384, 618-625 (2014)
DOI: 10.1016/S0140-6736(14)61217-4

58. E Bruckert, J Labreuche, P Amarenco: Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 210, 353-361 (2010)
DOI: 10.1016/j.atherosclerosis.2009.12.023

59. HPS2-THRIVE Collaborative Group, MJ Landray, R Haynes, JC Hopewell, S Parish, T Aung, J Tomson, K Wallendszus, M Craig, L Jiang, R Collins, J Armitage: Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 371, 203-212 (2014)
DOI: 10.1056/NEJMoa1300955

60. M Jun, C Foote, J Lv, B Neal, A Patel, SJ Nicholls, DE Grobbee, A Cass, J Chalmers, V Perkovic: Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 375, 1875-1884 (2010)
DOI: 10.1016/S0140-6736(10)60656-3

61. Administration FaD: Withdrawal of approval of indications related to the coadministration with statins in applications for niacin extended-release tablets and fenofibric acid delayed-release capsules. Fed Reg 81 (2016)

62. Administration FaD: Withdrawal of approval of new drug applications for Advicor and Simcor. Fed Reg 81 (2016)

63. C Li, W Zhang, F Zhou, C Chen, L Zhou, Y Li, L Liu, F Pei, H Luo, Z Hu, J Cai, C Zeng: Cholesteryl ester transfer protein inhibitors in the treatment of dyslipidemia: a systematic review and meta-analysis. PLoS One 8:e77049 (2013)
DOI: 10.1371/journal.pone.0077049

64. MJ Landray, Reveal Collaborative Group, L Bowman, F Chen, E Sammons, JC Hopewell, K Wallendszus, W Stevens, E Valdes-Marquez, S Wiviott, CP Cannon, E Braunwald, R Collins, MJ Landray (Writing Committtee): Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)-A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics. Am Heart J 187, 182-190 (2017)
DOI: 10.1016/j.ahj.2017.02.021

65. Emerging Risk Factors Collaboration: Lipid-related markers and cardiovascular disease prediction. JAMA 307, 2499-2506 (2012)

66. MJ Chapman, European Atherosclerosis Society Consensus Panel: Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 32, 1345-1361 (2011)
DOI: 10.1093/eurheartj/ehr112

67. RE Morton, L Izem: Modifcation of CETP function by changing its substrate preference: a new paradigm for CETP drug design. J Lipid Res 56, 612-619 (2015)
DOI: 10.1194/jlr.M056333

68. A von Eckardstein, L Rohrer: HDLs in crises. Curr Opin Lipidol 27, 264-273 (2016)
DOI: 10.1097/MOL.0000000000000294

69. G Silbernagel, B Schöttker, S Appelbaum, H Scharnagl, ME Kleber, TB Grammer, A Ritsch, U Mons, B Holleczek, G Goliasch, A Niessner, BO Boehm, RB Schnabel, H Brenner, S Blankenberg, U Landmesser, W März: High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality. Eur Heart J 34, 3563-3571 (2013)
DOI: 10.1093/eurheartj/eht343

70. W Annema, A von Eckardstein: Dysfunctional high- density lipoproteins in coronary heart disease: implications for diagnostics and therapy. Transl Res 173, 30-57 (2016)
DOI: 10.1016/j.trsl.2016.02.008

71. UP Steinbrecher, S Parthasarathy, DS Leake, JL Witztum, D Steinberg: Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A 81, 3883-3887 (1984)
DOI: 10.1073/pnas.81.12.3883

72. MF Prescott, KR Müller, R Flammer, U Feige: The effect of LDL and modified LDL on macrophage secretion products. Agents Actions Suppl 16, 163-170 (1984)
DOI: 10.1007/978-3-0348-7235-5_19

73. A Trpkovic, I Resanovic, J Stanimirovic, D Radak, SA Mousa, D Cenic-Milosevic, D Jevremovic, ER Isenovic: Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases. Crit Rev Clin Lab Sci 24, 1-16 (2014)

74. H Arai: Oxidative modification of lipoproteins. Subcell Biochem 77, 103-114 (2014)
DOI: 10.1007/978-94-007-7920-4_9

75. D Steinberg, JL Witztum: Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 30, 2311-2316 (2010)
DOI: 10.1161/ATVBAHA.108.179697

76. M Fukuchi, J Watanabe, K Kumagai, S Baba, T Shinozaki M, Miura, Y Kagaya, K Shirato: Normal and oxidized low density lipoproteins accumulate deep in physiologically thickened intima of human coronary arteries. Lab Invest 82, 1437-1447 (2002)
DOI: 10.1097/01.LAB.0000032546.01658.5D

77. H Itabe, T Obama, R Kato: The dynamics of oxidized LDL during atherogenesis. J Lipids 2011:418313 (2011)
DOI: 10.1155/2011/418313

78. W Palinski, ME Rosenfeld, S Ylä-Herttuala, GC Gurtner, SS Socher, SW Butler, S Parthasarathy, TE Carew, D Steinberg, JL Witztum: Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A 86, 1372-1376 (1989)
DOI: 10.1073/pnas.86.4.1372

79. S Ylä-Herttuala, W Palinski, ME Rosenfeld, D Steinberg, JL Witztum: Lipoproteins in normal and atherosclerotic aorta. Eur Heart J 11 Suppl E:88-99 (1990)

80. AN Orekhov, VV Tertov, AE Kabakov, IYu Adamova, SN Pokrovsky, VN Smirnov: Autoantibodies against modified low density lipoprotein Nonlipid factor of blood plasma that stimulates foam cell formation. Arterioscler Thromb 11, 316-326 (1991)
DOI: 10.1161/01.ATV.11.2.316

81. VV Tertov, VV Kaplun, IA Sobenin, AN Orekhov: Low-density lipoprotein modification occurring in human plasma possible mechanism of in vivo lipoprotein desialylation as a primary step of atherogenic modification. Atherosclerosis 138, 183-195 (1998)
DOI: 10.1016/S0021-9150(98)00023-9

82. EJ Mills, B Rachlis, P Wu, PJ Devereaux, P Arora, D Perri: Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 52, 1769-1781 (2008)
DOI: 10.1016/j.jacc.2008.08.039

83. K Berneis, C Jeanneret, J Muser, B Felix, AR Miserez: Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes. Metabolism 54, 227-234 (2005)
DOI: 10.1016/j.metabol.2004.08.017

84. DL Tribble, M Rizzo, A Chait, DM Lewis, PJ Blanche, RM Krauss: Enhanced oxidative susceptibility and reduced antioxidant content of metabolic precursors of small, dense low-density lipoproteins. Am J Med 110, 103-110 (2001)
DOI: 10.1016/S0002-9343(00)00700-2

85. M La Belle, RM Krauss: Differences in carbohydrate content of low density lipoproteins associated with low density lipoprotein subclass patterns. J Lipid Res 31, 1577-1588 (1990)

86. V Anber, BA Griffin, M McConnell, CJ Packard, J Shepherd: Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans. Atherosclerosis 124, 261-271 (1996)
DOI: 10.1016/0021-9150(96)05842-X

87. HF Hoff, JW Gaubatz: Isolation, purification, and characterization of a lipoprotein containing Apo B from the human aorta. Atherosclerosis 42, 273-297 (1982)
DOI: 10.1016/0021-9150(82)90157-5

88. CH Chen, T Jiang, JH Yang, W Jiang, J Lu, GK Marathe, HJ Pownall, CM Ballantyne, TM McIntyre, PD Henry, CY Yang: Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription. Circulation 107, 2102-2108 (2003)
DOI: 10.1161/01.CIR.0000065220.70220.F7

89. CY Yang, JL Raya, HH Chen, CH Chen, Y Abe, HJ Pownall, AA Taylor, CV Smith: Isolation, characterization, and functional assessment of oxidatively modified subfractions of circulating low-density lipoproteins. Arterioscler Thromb Vasc Biol 23, 1083-1090 (2003)
DOI: 10.1161/01.ATV.0000071350.78872.C4

90. D Tang, J Lu, JP Walterscheid, HH Chen, DA Engler, T Sawamura, PY Chang, HJ Safi, CY Yang, CH Chen: Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1. J Lipid Res 49, 33-47 (2008)
DOI: 10.1194/jlr.M700305-JLR200

91. HC Chan, LY Ke, CS Chu, AS Lee, MY Shen, MA Cruz, JF Hsu, KH Cheng, HC Chan, J Lu, WT Lai, T Sawamura, SH Sheu, JH Yen, CH Chen: Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation. Blood 122, 3632-3641 (2013)
DOI: 10.1182/blood-2013-05-504639

92. PY Chang, YJ Chen, FH Chang, J Lu, WH Huang, TC Yang, YT Lee, SF Chang, SC Lu, CH Chen: Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction. Cardiovasc Res 99, 137-145 (2013)
DOI: 10.1093/cvr/cvt062

93. T Parasassi, M De Spirito, G Mei, R Brunelli, G Greco, L Lenzi, G Maulucci, E Nicolai, M Papi, G Arcovito, SC Tosatto, F Ursini: Low density lipoprotein misfolding and amyloidogenesis. FASEB J 22, 2350-2356 (2008)
DOI: 10.1096/fj.07-097774

94. VV Tertov, IA Sobenin, ZA Gabbasov, EG Popov, AA Yaroslavov, M Jauhiainen, C Ehnholm, VN Smirnov, AN Orekhov: Three types of naturally occurring modified lipoproteins induce intracellular lipid accumulation in human aortic intimal cells--the role of lipoprotein aggregation. Eur J Clin Chem Clin Biochem 30, 300-308 (1992)
DOI: 10.1515/cclm.1992.30.4.171

95. VV Tertov, IA Sobenin, ZA Gabbasov, EG Popov, AN Orekhov: Lipoprotein aggregation as an essential condition of intracellular lipid accumulation caused by modified low density lipoproteins. Biochem Biophys Res Commun 163, 489-494 (1989)
DOI: 10.1016/0006-291X(89)92163-3

96. VV Tertov, AN Orekhov, IA Sobenin, ZA Gabbasov, EG Popov, AA Yaroslavov, VN Smirnov: Three types of naturally occurring modified lipoproteins induce intracellular lipid accumulation due to lipoprotein aggregation. Circ Res 71, 218-228 (1992)
DOI: 10.1161/01.RES.71.1.218

97. DV Aksenov, LA Medvedeva, TA Skalbe, IA Sobenin, VV Tertov, ZA Gabbasov, EV Popov, AN Orekhov: Deglycosylation of apo B-containing lipoproteins increase their ability to aggregate and to promote intracellular cholesterol accumulation in vitro. Arch Physiol Biochem 114, 349-356 (2008)
DOI: 10.1080/13813450802227915

98. T Parasassi, G Bittolo-Bon, R Brunelli, G Cazzolato, EK Krasnowska, G Mei, A Sevanian, F Ursini: Loss of apoB-100 secondary structure and conformation in hydroperoxide rich, electronegative LDL(-). Free Radic Biol Med 31, 82-89 (2001)
DOI: 10.1016/S0891-5849(01)00555-X

99. S Benítez, JL Sánchez-Quesada, L Lucero, R Arcelus, V Ribas, O Jorba, A Castellví, E Alonso, F Blanco-Vaca, J Ordóñez-Llanos: Changes in low-density lipoprotein electronegativity and oxidizability after aerobic exercise are related to the increase in associated non-esterified fatty acids. Atherosclerosis 160, 223-232 (2002)
DOI: 10.1016/S0021-9150(01)00565-2

100. JW Gaubatz, BK Gillard, JB Massey, RC Hoogeveen, M Huang, EE Lloyd, JL Raya, CY Yang, HJ Pownall: Dynamics of dense electronegative low density lipoproteins and their preferential association with lipoprotein phospholipase A(2). J Lipid Res 48, 348-357 (2007)
DOI: 10.1194/jlr.M600249-JLR200

101. S Jayaraman, DL Gantz, O Gursky: Effects of phospholipase A(2) and its products on structural stability of human LDL: relevance to formation of LDL-derived lipid droplets. Journal of lipid research 52, 549-557 (2011)
DOI: 10.1194/jlr.M012567

102. S Benítez, V Villegas, C Bancells, O Jorba, F González-Sastre, J Ordóñez-Llanos, JL Sánchez-Quesada: Impaired binding affinity of electronegative low-density lipoprotein (LDL) to the LDL receptor is related to nonesterified fatty acids and lysophosphatidylcholine content. Biochemistry 43, 15863-15872 (2004)
DOI: 10.1021/bi048825z

103. J Urata, S Ikeda, S Koga, T Nakata, T Yasunaga, K Sonoda, Y Koide, N Ashizawa, S Kohno and K Maemura: Negatively charged low-density lipoprotein is associated with atherogenic risk in hypertensive patients. Heart Vessels 27, 235-242 (2012)
DOI: 10.1007/s00380-011-0139-z

104. J Lu, JH Yang, AR Burns, HH Chen, D Tang, JP Walterscheid, S Suzuki, CY Yang, T Sawamura, CH Chen: Mediation of electronegative low-density lipoprotein signaling by LOX-1: a possible mechanism of endothelial apoptosis. Circ Res 104, 619-627 (2009)
DOI: 10.1161/CIRCRESAHA.108.190116

105. G Greco, G Balogh, R Brunelli, G Costa, M De Spirito, L Lenzi, G Mei, F Ursini and T Parasassi: Generation in human plasma of misfolded, aggregation-prone electronegative low density lipoprotein. Biophys J 97, 628-635 (2009)
DOI: 10.1016/j.bpj.2009.05.005

106. VV Tertov, AN Orekhov, ON Martsenyuk, NV Perova, VN Smirnov: Low-density lipoproteins isolated from the blood of patients with coronary heart disease induce the accumulation of lipids in human aortic cells. Exp Mol Pathol 50, 337-347 (1989)
DOI: 10.1016/0014-4800(89)90043-9

107. EI Chazov, VV Tertov, AN Orekhov, AA Lyakishev, NV Perova, KA Kurdanov, KA Khashimov, ID Novikov, VN Smirnov: Atherogenicity of blood serum from patients with coronary heart disease. Lancet 2, 595-598 (1986)
DOI: 10.1016/S0140-6736(86)92426-8

108. AN Orekhov, VV Tertov, DN Mukhin, IA Mikhailenko: Modification of low density lipoprotein by desialylation causes lipid accumulation in cultured cells: discovery of desialylated lipoprotein with altered cellular metabolism in the blood of atherosclerotic patients. Biochem Biophys Res Commun 162, 206-211 (1989)
DOI: 10.1016/0006-291X(89)91982-7

109. AN Orekhov, VV Tertov, DN Mukhin: Desialylated low density lipoprotein--naturally occurring modified lipoprotein with atherogenic potency. Atherosclerosis 86, 153-161 (1991)
DOI: 10.1016/0021-9150(91)90211-K

110. A. Ruelland, G Gallou, B Legras, F Paillard, L Cloarec: LDL sialic acid content in patients with coronary artery disease. Clin Chim Acta 221, 127-133 (1993)
DOI: 10.1016/0009-8981(93)90027-2

111. AL Bartlett, KK Stanley: All low density lipoprotein particles are partially desialylated in plasma. Atherosclerosis 138, 237-245 (1998)
DOI: 10.1016/S0021-9150(97)00288-8

112. VV Tertov, IA Sobenin, AN Orekhov: Are all low-density lipoprotein particles partially desialylated in plasma? Atherosclerosis 146, 391-394 (1999)

113. IA Sobenin, VV Tertov, AN Orekhov: Optimization of the assay for sialic acid determination in low density lipoprotein. J Lipid Res 39, 2293-2299 (1998)

114. VV Tertov, IA Sobenin, AN Orekhov: Modified (desialylated) low-density lipoprotein measured in serum by lectin-sorbent assay. Clin Chem 41, 1018-1021 (1995)

115. T Grewal, A Bartlett, JW Burgess, NH Packer, KK Stanley: Desialylated LDL uptake in human and mouse macrophages can be mediated by a lectin receptor. Atherosclerosis 121, 151-163 (1996)
DOI: 10.1016/0021-9150(95)05715-3

116. LM Harada, MD Carvalho, M Passarelli, EC Quintão: Lipoprotein desialylation simultaneously enhances the cell cholesterol uptake and impairs the reverse cholesterol transport system: in vitro evidences utilizing neuraminidase-treated lipoproteins and mouse peritoneal macrophages. Atherosclerosis 139, 65-75 (1998)
DOI: 10.1016/S0021-9150(98)00057-4

117. VV Tertov, IA Sobenin, AN Orekhov: Characterization of desialylated low-density lipoproteins which cause intracellular lipid accumulation. Int J Tissue React 14, 155-162 (1992)

118. VV Tertov, AN Orekhov: Metabolism of native and naturally occurring multiple modified low density lipoprotein in smooth muscle cells of human aortic intima. Exp Mol Pathol 64, 127-145 (1997)
DOI: 10.1006/exmp.1997.2216

119. VV Tertov, AN Orekhov, IA Sobenin, JD Morrisett, AM Gotto Jr, JG Guevara Jr: Carbohydrate composition of protein and lipid components in sialic acid-rich and -poor low density lipoproteins from subjects with and without coronary artery disease. J Lipid Res 34, 365-375 (1993)

120. VV Tertov, IA Sobenin, ZA Gabbasov, EG Popov, O Jaakkola, T Solakivi, T Nikkari, VN Smirnov, AN Orekhov: Multiple-modified desialylated low density lipoproteins that cause intracellular lipid accumulation Isolation, fractionation and characterization. Lab Invest 67, 665-675 (1992)

121. VV Tertov, VV Kaplun, SN Dvoryantsev, AN Orekhov: Apolipoprotein B-bound lipids as a marker for evaluation of low density lipoprotein oxidation in vivo. Biochem Biophys Res Commun 214, 608-613 (1995)
DOI: 10.1006/bbrc.1995.2329

122. AN Orekhov, VV Tertov, SA Kudryashov, VN Smirnov: Triggerlike stimulation of cholesterol accumulation and DNA and extracellular matrix synthesis induced by atherogenic serum or low density lipoprotein in cultured cells. Circ Res 66, 311-320 (1990)
DOI: 10.1161/01.RES.66.2.311

123. VV Tertov, AN Orekhov, LH Ryong, VN Smirnov: Intracellular cholesterol accumulation is accompanied by enhanced proliferative activity of human aortic intimal cells. Tissue Cell 20, 849-854 (1988)
DOI: 10.1016/0040-8166(88)90026-2

124. D Steinberg, TE Carew, C Fielding, AM Fogelman, RW Mahley, AD Sniderman, CB Zilversmit: Lipoproteins and the pathogenesis of atherosclerosis. Circulation 80, 719-723 (1989)
DOI: 10.1161/01.CIR.80.3.719

125. M Navab, AM Fogelman, JA Berliner, MC Territo, LL Demer, JS Frank, AD Watson, PA Edwards, AJ Lusis: Pathogenesis of atherosclerosis Am J Cardiol 76, 18C-23C (1995)
DOI: 10.1016/S0002-9149(99)80466-4

126. N Younis, R Sharma, H Soran, V Charlton-Menys, M Elseweidy, PN Durrington: Glycation as an atherogenic modification of LDL. Curr Opin Lipidol 19, 378-384 (2008)
DOI: 10.1097/MOL.0b013e328306a057

127. H Soran, PN Durrington: Susceptibility of LDL and its subfractions to glycation. Curr Opin Lipidol 22, 254-261 (2011)
DOI: 10.1097/MOL.0b013e328348a43f

128. ER Zakiev, IA Sobenin, VN Sukhorukov, VA Myasoedova, EA Ivanova, AN Orekhov: Carbohydrate composition of circulating multiple-modified low-density lipoprotein. Vasc Health Risk Manag 12, 379-385 (2016)
DOI: 10.2147/VHRM.S112948

129. ER Zakiev, VN Sukhorukov, EA Ivanova, AN Orekhov: Analysis of apolipoprotein B protein of circulating multiple-modified low-density lipoprotein. Int J Angiol 26, 49-52 (2017)
DOI: 10.1055/s-0036-1588062

130. VV Tertov, VV Kaplun, IA Sobenin, EY Boytsova, NV Bovin, AN Orekhov: Human plasma trans-sialidase causes atherogenic modification of low density lipoprotein. Atherosclerosis 159, 103-115 (2001)
DOI: 10.1016/S0021-9150(01)00498-1

131. N Dousset, JC Dousset, ML Soléra, P Valdiguié: Desialylated low density lipoproteins and atherosclerosis. EXS 62, 158-163 (1992)
DOI: 10.1007/978-3-0348-7460-1_16

132. AN Orekhov, VV Tertov, DN Mukhin: Desialylated low density lipoprotein - naturally occurring modified lipoprotein with atherogenic potency. Atherosclerosis 86, 153-161 (1991)
DOI: 10.1016/0021-9150(91)90211-K

133. S Tsimikas, YI Miller: Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. Curr Pharm Des 17, 27-37 (2011)
DOI: 10.2174/138161211795049831

134. A Trpkovic, I Resanovic, J Stanimirovic, D Radak, SA Mousa, D Cenic-Milosevic, D Jevremovic, ER Isenovic: Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases. Crit Rev Clin Lab Sci 52, 70-85 (2015)
DOI: 10.3109/10408363.2014.992063

135. W März, MW Baumstark, H Scharnagl, V Ruzicka, S Buxbaum, J Herwig, T Pohl, A Russ, L Schaaf, A Berg: Accumulation of “small dense” low density lipoproteins (LDL) in a homozygous patients with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor J Clin Invest 92, 2922-2933 (1993)
DOI: 10.1172/JCI116915

136. M Tani, A Kawakami, Y Mizuno, R Imase, Y Ito, K Kondo, H Ishii, M Yoshida: Small dense LDL enhances THP-1 macrophage foam cell formation. J Atheroscler Thromb 18, 698-704 (2011)
DOI: 10.5551/jat.7161

137. VN Sukhorukov, VP Karagodin, AN Orekhov: Atherogenic modification of low-density lipoproteins. Biomed Khim 62, 391-402 (2016)
DOI: 10.18097/pbmc20166204391

138. EA Ivanova, VA Myasoedova, AA Melnichenko, AV Grechko, AN Orekhov: Small dense low-density lipoprotein as biomarker for atherosclerotic diseases. Oxid Med Cell Longev 2017, 1273042 (2017)
DOI: 10.1155/2017/1273042

139. M Estruch, JL Sánchez-Quesada, J Ordóñez Llanos, S Benítez: Electronegative LDL: a circulating modified LDL with a role in inflammation. Mediators Inflamm 2013, 181324 (2013)
DOI: 10.1155/2013/181324

140. VV Tertov, G Bittolo-Bon, IA Sobenin, G Cazzolato, AN Orekhov, P Avogaro: Naturally occurring modified low density lipoproteins are similar if not identical: more electronegative and desialylated lipoprotein subfractions. Exp Mol Pathol 62, 166-172 (1995)
DOI: 10.1006/exmp.1995.1018

141. E Köko─člu, S Süer, H Sönmez, N Uçişik: The relationship between the electrophoretic mobility of lipoproteins and coronary heart disease. Res Commun Mol Pathol Pharmacol 91, 109-116 (1996)

142. B Garner, DJ Harvey, L Royle, M Frischmann, F Nigon, MJ Chapman, PM Rudd: Characterization of human apolipoprotein B100 oligosaccharides in LDL subfractions derived from normal and hyperlipidemic plasma: deficiency of alpha-N-acetylneuraminyllactosyl-ceramide in light and small dense LDL particles. Glycobiology 11, 791-802 (2001)
DOI: 10.1093/glycob/11.10.791

143. IA Sobenin, EV Galitsyna, AV Grechko, AN Orekhov: Small dense and desialylated low density lipoprotein in diabetic patients. Vessel Plus 1, 29-37 (2017)
DOI: 10.20517/2574-1209.2016.12

144. AN Orekhov, EM Pivovarova, IA Sobenin, VV Yakushkin, VV Tertov: Use of cell culture for optimisation of direct antiatherogenic therapy with verapamil. Drugs 44 Suppl 1, 105-110 (1992)
DOI: 10.2165/00003495-199200441-00020

145. AN Orekhov, IA Sobenin, MA Gavrilin, A Gratchev, SY Kotyashova, NG Nikiforov, J Kzhyshkowska: Macrophages in immunopathology of atherosclerosis: a target for diagnostics and therapy Curr Pharm Des 21, 1172-1179 (2015)
DOI: 10.2174/1381612820666141013120459

146. M Lee-Rueckert, JC Escola-Gil, PT Kovanen: HDL functionality in reverse cholesterol transport--Challenges in translating data emerging from mouse models to human disease. Biochim Biophys Acta 1861, 566-583 (2016)
DOI: 10.1016/j.bbalip.2016.03.004

147. JA Leopold: Antioxidants and coronary artery disease: from pathophysiology to preventive therapy. Coron Artery Dis 26, 176-183 (2015)
DOI: 10.1097/MCA.0000000000000187

148. American Heart Association Nutrition Committee, AH Lichtenstein, LJ Appel, M Brands, M Carnethon, S Daniels, HA Franch, B Franklin, P Kris-Etherton, WS Harris, B Howard, N Karanja, M Lefevre, L Rudel, F Sacks, L Van Horn, M Winston, J Wylie-Rosett: Diet and lifestyle recommendations revision 2006: A scientific statement from the American Heart Association Nutrition Committee. Circulation 114, 82–96 (2006)
DOI: 10.1161/CIRCULATIONAHA.106.176158

149. VV Tertov, VV Kaplun, IA Sobenin, AN Orekhov: Low-density lipoprotein modification occurring in human plasma possible mechanism of in vivo lipoprotein desialylation as a primary step of atherogenic modification. Atherosclerosis 138, 183-195 (1998)
DOI: 10.1016/S0021-9150(98)00023-9

150. IA Sobenin, JT Salonen, AV Zhelankin, AA Melnichenko, J Kaikkonen, YV Bobryshev, AN Orekhov: Low density lipoprotein-containing circulating immune complexes: role in atherosclerosis and diagnostic value. Biomed Res Int 2014, 205697 (2014)
DOI: 10.1155/2014/205697

151. IA Sobenin, VP Karagodin, AC Melnichenko, YV Bobryshev, AN Orekhov: Diagnostic and prognostic value of low density lipoprotein-containing circulating immune complexes in atherosclerosis. J Clin Immunol 33, 489-495 (2013)
DOI: 10.1007/s10875-012-9819-4

152. VV Tertov, IA Sobenin, AN Orekhov, O Jaakkola, T Solakivi, T Nikkari: Characteristics of low density lipoprotein isolated from circulating immune complexes. Atherosclerosis 122, 191-199 (1996)
DOI: 10.1016/0021-9150(95)05737-4

153. AG Kacharava, VV Tertov, AN Orekhov: Autoantibodies against low-density lipoprotein and atherogenic potential of blood. Ann Med 25, 551-555 (1993)

154. AN Orekhov, OS Kalenich, VV Tertov, ID Novikov: Lipoprotein immune complexes as markers of atherosclerosis. Int J Tissue React 13, 233-236 (1991)

155. AN Orekhov, VV Tertov, DN Mukhin, VE Koteliansky, MA Glukhova, KA Khashimov, VN Smirnov: Association of low-density lipoprotein with particulate connective tissue matrix components enhances cholesterol accumulation in cultured subendothelial cells of human aorta. Biochim Biophys Acta 928, 251-258 (1987)
DOI: 10.1016/0167-4889(87)90183-2

156. AN Orekhov, VV Tertov, DN Mukhin, VE Koteliansky, MA Glukhova, MG Frid, GK Sukhova, KA Khashimov, VN Smirnov: Insolubilization of low density lipoprotein induces cholesterol accumulation in cultured subendothelial cells of human aorta. Atherosclerosis 79, 59-70 (1989)
DOI: 10.1016/0021-9150(89)90034-8

157. P Collinson: Evidence and cost effectiveness requirements for recommending new biomarkers. EJIFCC 26, 183-189 (2015)

Key Words: Atherosclerosis; cardiovascular disease; LDL; HDL; modified LDL; lipidosis

Send correspondence to: Alexander N. Orekhov, Institute for Atherosclerosis Research, Skolkovo Innovative Center, Russian Federation, 143025 Moscow, Russia, Tel: +7 903 169 08 66, Fax: +7 903 169 08 66, E-mail: a.h.opexob@gmail.com