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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Electronegative LDL: An Active Player in Atherogenesis or a By- Product of Atherosclerosis?

Author(s): Andrea Rivas-Urbina, Anna Rull, Jordi Ordóñez-Llanos and José Luis Sánchez-Quesada*

Volume 26, Issue 9, 2019

Page: [1665 - 1679] Pages: 15

DOI: 10.2174/0929867325666180330093953

Price: $65

Abstract

Low-density lipoproteins (LDLs) are the major plasma carriers of cholesterol. However, LDL particles must undergo various molecular modifications to promote the development of atherosclerotic lesions. Modified LDL can be generated by different mechanisms, but as a common trait, show an increased electronegative charge of the LDL particle. A subfraction of LDL with increased electronegative charge (LDL(-)), which can be isolated from blood, exhibits several pro-atherogenic characteristics. LDL(-) is heterogeneous, due to its multiple origins but is strongly related to the development of atherosclerosis. Nevertheless, the implication of LDL(-) in a broad array of pathologic conditions is complex and in some cases anti-atherogenic LDL(-) properties have been reported. In fact, several molecular modifications generating LDL(-) have been widely studied, but it remains unknown as to whether these different mechanisms are specific or common to different pathological disorders. In this review, we attempt to address these issues examining the most recent findings on the biology of LDL(-) and discussing the relationship between this LDL subfraction and the development of different diseases with increased cardiovascular risk. Finally, the review highlights the importance of minor apolipoproteins associated with LDL(-) which would play a crucial role in the different properties displayed by these modified LDL particles.

Keywords: Electronegative LDL, L5, LDL modification, atherosclerosis, inflammation, apoptosis, lipoprotein aggregation.

[1]
Berliner, J.A.; Navab, M.; Fogelman, A.M.; Frank, J.S.; Demer, L.L.; Edwards, P.A.; Watson, A.D.; Lusis, A.J. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation, 1995, 91(9), 2488-2496.
[2]
Steinberg, D. The LDL modification hypothesis of atherogenesis: An update. J. Lipid Res., 2009, 50(Suppl.), S376-S381.
[3]
Sánchez-Quesada, J.L.; Villegas, S. Modified forms of LDL in plasma; Atherogenesis, 2012, pp. 447-472.
[4]
Avogaro, P.; Bon, G.B.; Cazzolato, G. Presence of a modified low density lipoprotein in humans. Arteriosclerosis, 1988, 8(1), 79-87.
[5]
Avogaro, P.; Cazzolato, G.; Bittolo-Bon, G. Some questions concerning a small, more electronegative LDL circulating in human plasma. Atherosclerosis, 1991, 91(1-2), 163-171.
[6]
Cazzolato, G.; Avogaro, P.; Bittolo-Bon, G. Characterization of a more electronegatively charged LDL subfraction by ion exchange HPLC. Free Radic. Biol. Med., 1991, 11(3), 247-253.
[7]
Akyol, S.; Lu, J.; Akyol, O.; Akcay, F.; Armutcu, F.; Ke, L.Y.; Chen, C.H. The role of electronegative low-density lipoprotein in cardiovascular diseases and its therapeutic implications. Trends Cardiovasc. Med., 2017, 27(4), 239-246.
[8]
Mello, A.P.; da Silva, I.T.; Abdalla, D.S.; Damasceno, N.R. Electronegative low-density lipoprotein: Origin and impact on health and disease. Atherosclerosis, 2011, 215(2), 257-265.
[9]
Sánchez-Quesada, J.L.; Benítez, S.; Ordóñez-Llanos, J. Electronegative low-density lipoprotein. Curr. Opin. Lipidol., 2004, 15(3), 329-335.
[10]
Sanchez-Quesada, J.L.; Estruch, M.; Benitez, S.; Ordonez-Llanos, J.; Electronegative, L.D.L. A useful marker of cardiovascular risk? Clin. Lipidol., 2012, 7(3), 345-359.
[11]
Ke, L.Y.; Stancel, N.; Bair, H.; Chen, C.H. The underlying chemistry of electronegative LDL’s atherogenicity. Curr. Atheroscler. Rep., 2014, 16(8), 428.
[12]
Sánchez-Quesada, J.L.; Otal-Entraigas, C.; Franco, M.; Jorba, O.; González-Sastre, F.; Blanco-Vaca, F.; Ordóñez-Llanos, J. Effect of simvastatin treatment on the electronegative low-density lipoprotein present in patients with heterozygous familial hypercholesterolemia. Am. J. Cardiol., 1999, 84(6), 655-659.
[13]
Chen, H.H.; Hosken, B.D.; Huang, M.; Gaubatz, J.W.; Myers, C.L.; Macfarlane, R.D.; Pownall, H.J.; Yang, C.Y. Electronegative LDLs from familial hypercholesterolemic patients are physicochemically heterogeneous but uniformly proapoptotic. J. Lipid Res., 2007, 48(1), 177-184.
[14]
Zhang, B.; Matsunaga, A.; Rainwater, D.L.; Miura, S.; Noda, K.; Nishikawa, H.; Uehara, Y.; Shirai, K.; Ogawa, M.; Saku, K. Effects of rosuvastatin on electronegative LDL as characterized by capillary isotachophoresis: The ROSARY Study. J. Lipid Res., 2009, 50(9), 1832-1841.
[15]
Chu, C.S.; Ke, L.Y.; Chan, H.C.; Chan, H.C.; Chen, C.C.; Cheng, K.H.; Lee, H.C.; Kuo, H.F.; Chang, C.T.; Chang, K.C.; Sheu, S.H.; Chen, C.H.; Lai, W.T. Four Statin Benefit Groups Defined by The 2013 ACC/AHA New Cholesterol Guideline are Characterized by Increased Plasma Level of Electronegative Low-Density Lipoprotein. Acta Cardiol Sin, 2016, 32(6), 667-675.
[16]
Sánchez-Quesada, J.L.; Benítez, S.; Otal, C.; Franco, M.; Blanco-Vaca, F.; Ordóñez-Llanos, J. Density distribution of electronegative LDL in normolipemic and hyperlipemic subjects. J. Lipid Res., 2002, 43(5), 699-705.
[17]
Sánchez-Quesada, J.L.; Pérez, A.; Caixàs, A.; Rigla, M.; Payés, A.; Benítez, S.; Ordóñez-Llanos, J. Effect of glycemic optimization on electronegative low-density lipoprotein in diabetes: Relation to nonenzymatic glycosylation and oxidative modification. J. Clin. Endocrinol. Metab., 2001, 86(7), 3243-3249.
[18]
Moro, E.; Zambon, C.; Pianetti, S.; Cazzolato, G.; Pais, M.; Bittolo Bon, G. Electronegative low density lipoprotein subform (LDL-) is increased in type 2 (non-insulin-dependent) microalbuminuric diabetic patients and is closely associated with LDL susceptibility to oxidation. Acta Diabetol., 1998, 35(3), 161-164.
[19]
Yang, C.Y.; Chen, H.H.; Huang, M.T.; Raya, J.L.; Yang, J.H.; Chen, C.H.; Gaubatz, J.W.; Pownall, H.J.; Taylor, A.A.; Ballantyne, C.M.; Jenniskens, F.A.; Smith, C.V. Pro-apoptotic low-density lipoprotein subfractions in type II diabetes. Atherosclerosis, 2007, 193(2), 283-291.
[20]
Sánchez-Quesada, J.L.; Pérez, A.; Caixàs, A.; Ordónmez-Llanos, J.; Carreras, G.; Payés, A.; González-Sastre, F.; de Leiva, A. Electronegative low density lipoprotein subform is increased in patients with short-duration IDDM and is closely related to glycaemic control. Diabetologia, 1996, 39(12), 1469-1476.
[21]
Sánchez-Quesada, J.L.; Vinagre, I.; de Juan-Franco, E.; Sánchez-Hernández, J.; Blanco-Vaca, F.; Ordóñez-Llanos, J.; Pérez, A. Effect of improving glycemic control in patients with type 2 diabetes mellitus on low-density lipoprotein size, electronegative low-density lipoprotein and lipoprotein-associated phospholipase A2 distribution. Am. J. Cardiol., 2012, 110(1), 67-71.
[22]
Yano, M.; Inoue, M.; Maehata, E.; Shiba, T.; Yamakado, M.; Hirabayashi, Y.; Taniyama, M.; Suzuki, S. Increased electronegative charge of serum low-density lipoprotein in patients with diabetes mellitus. Clin. Chim. Acta, 2004, 340(1-2), 93-98.
[23]
Zhang, B.; Kaneshi, T.; Ohta, T.; Saku, K. Relation between insulin resistance and fast-migrating LDL subfraction as characterized by capillary isotachophoresis. J. Lipid Res., 2005, 46(10), 2265-2277.
[24]
Apolinario, E.; Ferderbar, S.; Pereira, E.C.; Bertolami, M.C.; Faludi, A.; Monte, O.; Gagliardi, A.R.; Xavier, H.T.; Abdalla, D.S. Minimally modified (electronegative) LDL- and anti-LDL- autoantibodies in diabetes mellitus and impaired glucose tolerance. Int J Atheroscler, 2006, 1(1), 42-47.
[25]
Hsu, J.F.; Chou, T.C.; Lu, J.; Chen, S.H.; Chen, F.Y.; Chen, C.C.; Chen, J.L.; Elayda, M.; Ballantyne, C.M.; Shayani, S.; Chen, C.H. Low-density lipoprotein electronegativity is a novel cardiometabolic risk factor. PLoS One, 2014, 9(9), e107340.
[26]
Lee, A.S.; Chen, W.Y.; Chan, H.C.; Hsu, J.F.; Shen, M.Y.; Chang, C.M.; Bair, H.; Su, M.J.; Chang, K.C.; Chen, C.H. Gender disparity in LDL-induced cardiovascular damage and the protective role of estrogens against electronegative LDL. Cardiovasc. Diabetol., 2014, 13, 64.
[27]
Park, H.; Ishigami, A.; Shima, T.; Mizuno, M.; Maruyama, N.; Yamaguchi, K.; Mitsuyoshi, H.; Minami, M.; Yasui, K.; Itoh, Y.; Yoshikawa, T.; Fukui, M.; Hasegawa, G.; Nakamura, N.; Ohta, M.; Obayashi, H.; Okanoue, T. Hepatic senescence marker protein-30 is involved in the progression of nonalcoholic fatty liver disease. J. Gastroenterol., 2010, 45(4), 426-434.
[28]
Park, H.; Shima, T.; Yamaguchi, K.; Mitsuyoshi, H.; Minami, M.; Yasui, K.; Itoh, Y.; Yoshikawa, T.; Fukui, M.; Hasegawa, G.; Nakamura, N.; Ohta, M.; Obayashi, H.; Okanoue, T. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J. Gastroenterol., 2011, 46(1), 101-107.
[29]
Ziouzenkova, O.; Sevanian, A. Oxidative modification of low-density lipoprotein (LDL) in HD patients: Role in electronegative LDL formation. Blood Purif., 2000, 18(3), 169-176.
[30]
Lobo, J.C.; Mafra, D.; Farage, N.E. Faulin, Tdo.E.; Abdalla, D.S.; de Nóbrega, A.C.; Torres, J.P. Increased electronegative LDL and decreased antibodies against electronegative LDL levels correlate with inflammatory markers and adhesion molecules in hemodialysed patients. Clin. Chim. Acta, 2011, 412(19-20), 1788-1792.
[31]
Chang, C.T.; Wang, G.J.; Kuo, C.C.; Hsieh, J.Y.; Lee, A.S.; Chang, C.M.; Wang, C.C.; Shen, M.Y.; Huang, C.C.; Sawamura, T.; Yang, C.Y.; Stancel, N.; Chen, C.H. Electronegative low-density lipoprotein increases coronary artery disease risk in uremia patients on maintenance hemodialysis. Medicine (Baltimore), 2016, 95(2), e2265.
[32]
Tang, D.; Lu, J.; Walterscheid, J.P.; Chen, H.H.; Engler, D.A.; Sawamura, T.; Chang, P.Y.; Safi, H.J.; Yang, C.Y.; Chen, C.H. Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1. J. Lipid Res., 2008, 49(1), 33-47.
[33]
Ursini, F.; Zamburlini, A.; Cazzolato, G.; Maiorino, M.; Bon, G.B.; Sevanian, A. Postprandial plasma lipid hydroperoxides: a possible link between diet and atherosclerosis. Free Radic. Biol. Med., 1998, 25(2), 250-252.
[34]
Benítez, S.; Sánchez-Quesada, J.L.; Lucero, L.; Arcelus, R.; Ribas, V.; Jorba, O.; Castellví, A.; Alonso, E.; Blanco-Vaca, F.; Ordóñez-Llanos, J. Changes in low-density lipoprotein electronegativity and oxidizability after aerobic exercise are related to the increase in associated non-esterified fatty acids. Atherosclerosis, 2002, 160(1), 223-232.
[35]
Niccoli, G.; Bacà, M.; De Spirito, M.; Parasassi, T.; Cosentino, N.; Greco, G.; Conte, M.; Montone, R.A.; Arcovito, G.; Crea, F. Impact of electronegative low-density lipoprotein on angiographic coronary atherosclerotic burden. Atherosclerosis, 2012, 223(1), 166-170.
[36]
Oliveira, J.A.; Sevanian, A.; Rodrigues, R.J.; Apolinário, E.; Abdalla, D.S. Minimally modified electronegative LDL and its autoantibodies in acute and chronic coronary syndromes. Clin. Biochem., 2006, 39(7), 708-714.
[37]
Tomasik, A.; Jacheć, W.; Skrzep-Poloczek, B.; Widera-Romuk, E.; Wodniecki, J.; Wojciechowska, C. Circulating electronegatively charged low-density lipoprotein in patients with angiographically documented coronary artery disease. Scand. J. Clin. Lab. Invest., 2003, 63(4), 259-265.
[38]
Chan, H.C.; Ke, L.Y.; Chu, C.S.; Lee, A.S.; Shen, M.Y.; Cruz, M.A.; Hsu, J.F.; Cheng, K.H.; Chan, H.C.; Lu, J.; Lai, W.T.; Sawamura, T.; Sheu, S.H.; Yen, J.H.; Chen, C.H. Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation. Blood, 2013, 122(22), 3632-3641.
[39]
Chang, P.Y.; Chen, Y.J.; Chang, F.H.; Lu, J.; Huang, W.H.; Yang, T.C.; Lee, Y.T.; Chang, S.F.; Lu, S.C.; Chen, C.H. 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., 2013, 99(1), 137-145.
[40]
Shen, M.Y.; Chen, F.Y.; Hsu, J.F.; Fu, R.H.; Chang, C.M.; Chang, C.T.; Liu, C.H.; Wu, J.R.; Lee, A.S.; Chan, H.C.; Sheu, J.R.; Lin, S.Z.; Shyu, W.C.; Sawamura, T.; Chang, K.C.; Hsu, C.Y.; Chen, C.H. Plasma L5 levels are elevated in ischemic stroke patients and enhance platelet aggregation. Blood, 2016, 127(10), 1336-1345.
[41]
Ishigaki, Y.; Oka, Y.; Katagiri, H. Circulating oxidized LDL: A biomarker and a pathogenic factor. Curr. Opin. Lipidol., 2009, 20(5), 363-369.
[42]
Brownlee, M. Negative consequences of glycation. Metabolism, 2000, 49(2)(Suppl. 1), 9-13.
[43]
Oztürk, Z.; Sönmez, H.; Görgün, F.M.; Ekmekçi, H.; Bilgen, D.; Ozen, N.; Sözer, V.; Altuğ, T.; Kökoğlu, E. The relationship between lipid peroxidation and LDL desialylation in experimental atherosclerosis. Toxicol. Mech. Methods, 2007, 17(5), 265-273.
[44]
Ivanova, E.A.; Bobryshev, Y.V.; Orekhov, A.N. LDL electronegativity index: A potential novel index for predicting cardiovascular disease. Vasc. Health Risk Manag., 2015, 11, 525-532.
[45]
Zakiev, E.R.; Sukhorukov, V.N.; Melnichenko, A.A.; Sobenin, I.A.; Ivanova, E.A.; Orekhov, A.N. Lipid composition of circulating multiple-modified low density lipoprotein. Lipids Health Dis., 2016, 15(1), 134.
[46]
Tertov, V.V.; Bittolo-Bon, G.; Sobenin, I.A.; Cazzolato, G.; Orekhov, A.N.; Avogaro, P. Naturally occurring modified low density lipoproteins are similar if not identical: More electronegative and desialylated lipoprotein subfractions. Exp. Mol. Pathol., 1995, 62(3), 166-172.
[47]
Basnakian, A.G.; Shah, S.V.; Ok, E.; Altunel, E.; Apostolov, E.O.; Carbamylated, L.D.L. Carbamylated LDL. Adv. Clin. Chem., 2010, 51, 25-52.
[48]
Verbrugge, F.H.; Tang, W.H.; Hazen, S.L. Protein carbamylation and cardiovascular disease. Kidney Int., 2015, 88(3), 474-478.
[49]
Gaubatz, J.W.; Gillard, B.K.; Massey, J.B.; Hoogeveen, R.C.; Huang, M.; Lloyd, E.E.; Raya, J.L.; Yang, C.Y.; Pownall, H.J. Dynamics of dense electronegative low density lipoproteins and their preferential association with lipoprotein phospholipase A(2). J. Lipid Res., 2007, 48(2), 348-357.
[50]
Sevanian, A.; Hwang, J.; Hodis, H.; Cazzolato, G.; Avogaro, P.; Bittolo-Bon, G. Contribution of an in vivo oxidized LDL to LDL oxidation and its association with dense LDL subpopulations. Arterioscler. Thromb. Vasc. Biol., 1996, 16(6), 784-793.
[51]
Lund-Katz, S.; Laplaud, P.M.; Phillips, M.C.; Chapman, M.J. Apolipoprotein B-100 conformation and particle surface charge in human LDL subspecies: implication for LDL receptor interaction. Biochemistry, 1998, 37(37), 12867-12874.
[52]
Reaven, P.D.; Herold, D.A.; Barnett, J.; Edelman, S. Effects of Vitamin E on susceptibility of low-density lipoprotein and low-density lipoprotein subfractions to oxidation and on protein glycation in NIDDM. Diabetes Care, 1995, 18(6), 807-816.
[53]
Tribble, D.L. Lipoprotein oxidation in dyslipidemia: Insights into general mechanisms affecting lipoprotein oxidative behavior. Curr. Opin. Lipidol., 1995, 6(4), 196-208.
[54]
Younis, N.; Charlton-Menys, V.; Sharma, R.; Soran, H.; Durrington, P.N. Glycation of LDL in non-diabetic people: Small dense LDL is preferentially glycated both in vivo and in vitro. Atherosclerosis, 2009, 202(1), 162-168.
[55]
Younis, N.; Sharma, R.; Soran, H.; Charlton-Menys, V.; Elseweidy, M.; Durrington, P.N. Glycation as an atherogenic modification of LDL. Curr. Opin. Lipidol., 2008, 19(4), 378-384.
[56]
Krauss, R.M. Heterogeneity of plasma low-density lipoproteins and atherosclerosis risk. Curr. Opin. Lipidol., 1994, 5(5), 339-349.
[57]
Diffenderfer, M.R.; Schaefer, E.J. The composition and metabolism of large and small LDL. Curr. Opin. Lipidol., 2014, 25(3), 221-226.
[58]
Benítez, S.; Camacho, M.; Arcelus, R.; Vila, L.; Bancells, C.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. Increased lysophosphatidylcholine and non-esterified fatty acid content in LDL induces chemokine release in endothelial cells. Relationship with electronegative LDL. Atherosclerosis, 2004, 177(2), 299-305.
[59]
Benítez, S.; Villegas, V.; Bancells, C.; Jorba, O.; González-Sastre, F.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. Impaired binding affinity of electronegative low-density lipoprotein (LDL) to the LDL receptor is related to nonesterified fatty acids and lysophosphatidylcholine content. Biochemistry, 2004, 43(50), 15863-15872.
[60]
Jayaraman, S.; Gantz, D.L.; Gursky, O. Effects of phospholipase A(2) and its products on structural stability of human LDL: Relevance to formation of LDL-derived lipid droplets. J. Lipid Res., 2011, 52(3), 549-557.
[61]
Yang, T.C.; Chang, P.Y.; Lu, S.C. L5-LDL from ST-elevation myocardial infarction patients induces IL-1β production via LOX-1 and NLRP3 inflammasome activation in macrophages. Am. J. Physiol. Heart Circ. Physiol., 2017, 312(2), H265-H274.
[62]
Yang, C.Y.; Raya, J.L.; Chen, H.H.; Chen, C.H.; Abe, Y.; Pownall, H.J.; Taylor, A.A.; Smith, C.V. Isolation, characterization, and functional assessment of oxidatively modified subfractions of circulating low-density lipoproteins. Arterioscler. Thromb. Vasc. Biol., 2003, 23(6), 1083-1090.
[63]
Chen, C.H.; Jiang, T.; Yang, J.H.; Jiang, W.; Lu, J.; Marathe, G.K.; Pownall, H.J.; Ballantyne, C.M.; McIntyre, T.M.; Henry, P.D.; Yang, C.Y. Low-density lipoprotein in hypercholesterolemic human plasma induces vascular endothelial cell apoptosis by inhibiting fibroblast growth factor 2 transcription. Circulation, 2003, 107(16), 2102-2108.
[64]
Benítez, S.; Camacho, M.; Bancells, C.; Vila, L.; Sánchez-Quesada, J.L.; Ordóñez-Llanos, J. Wide proinflammatory effect of electronegative low-density lipoprotein on human endothelial cells assayed by a protein array. Biochim. Biophys. Acta, 2006, 1761(9), 1014-1021.
[65]
de Castellarnau, C.; Bancells, C.; Benítez, S.; Reina, M.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. Atherogenic and inflammatory profile of human arterial endothelial cells (HUAEC) in response to LDL subfractions. Clin. Chim. Acta, 2007, 376(1-2), 233-236.
[66]
De Castellarnau, C.; Sánchez-Quesada, J.L.; Benítez, S.; Rosa, R.; Caveda, L.; Vila, L.; Ordóñez-Llanos, J. Electronegative LDL from normolipemic subjects induces IL-8 and monocyte chemotactic protein secretion by human endothelial cells. Arterioscler. Thromb. Vasc. Biol., 2000, 20(10), 2281-2287.
[67]
Lee, A.S.; Wang, G.J.; Chan, H.C.; Chen, F.Y.; Chang, C.M.; Yang, C.Y.; Lee, Y.T.; Chang, K.C.; Chen, C.H. Electronegative low-density lipoprotein induces cardiomyocyte apoptosis indirectly through endothelial cell-released chemokines. Apoptosis, 2012, 17(9), 1009-1018.
[68]
Ziouzenkova, O.; Asatryan, L.; Sahady, D.; Orasanu, G.; Perrey, S.; Cutak, B.; Hassell, T.; Akiyama, T.E.; Berger, J.P.; Sevanian, A.; Plutzky, J. Dual roles for lipolysis and oxidation in peroxisome proliferation-activator receptor responses to electronegative low density lipoprotein. J. Biol. Chem., 2003, 278(41), 39874-39881.
[69]
Estruch, M.; Bancells, C.; Beloki, L.; Sanchez-Quesada, J.L.; Ordóñez-Llanos, J.; Benitez, S. CD14 and TLR4 mediate cytokine release promoted by electronegative LDL in monocytes. Atherosclerosis, 2013, 229(2), 356-362.
[70]
Estruch, M.; Rajamäki, K.; Sanchez-Quesada, J.L.; Kovanen, P.T.; Öörni, K.; Benitez, S.; Ordoñez-Llanos, J. Electronegative LDL induces priming and inflammasome activation leading to IL-1β release in human monocytes and macrophages. Biochim. Biophys. Acta, 2015, 1851(11), 1442-1449.
[71]
Estruch, M.; Sanchez-Quesada, J.L.; Ordoñez-Llanos, J.; Benitez, S. Inflammatory intracellular pathways activated by electronegative LDL in monocytes. Biochim. Biophys. Acta, 2016, 1861(9 Pt A), 963-969.
[72]
Abe, Y.; Fornage, M.; Yang, C.Y.; Bui-Thanh, N.A.; Wise, V.; Chen, H.H.; Rangaraj, G.; Ballantyne, C.M. L5, the most electronegative subfraction of plasma LDL, induces endothelial vascular cell adhesion molecule 1 and CXC chemokines, which mediate mononuclear leukocyte adhesion. Atherosclerosis, 2007, 192(1), 56-66.
[73]
Estruch, M.; Sánchez-Quesada, J.L.; Ordóñez Llanos, J.; Benítez, S.; Electronegative, L.D.L. Electronegative LDL: A circulating modified LDL with a role in inflammation. Mediators Inflamm., 2013, 2013, 181324.
[74]
Yu, L.E.; Lai, C.L.; Lee, C.T.; Wang, J.Y. Highly electronegative low-density lipoprotein L5 evokes microglial activation and creates a neuroinflammatory stress via Toll-like receptor 4 signaling. J. Neurochem., 2017, 142(2), 231-245.
[75]
Chu, C.S.; Wang, Y.C.; Lu, L.S.; Walton, B.; Yilmaz, H.R.; Huang, R.Y.; Sawamura, T.; Dixon, R.A.; Lai, W.T.; Chen, C.H.; Lu, J. Electronegative low-density lipoprotein increases C-reactive protein expression in vascular endothelial cells through the LOX-1 receptor. PLoS One, 2013, 8(8), e70533.
[76]
Lu, J.; Jiang, W.; Yang, J.H.; Chang, P.Y.; Walterscheid, J.P.; Chen, H.H.; Marcelli, M.; Tang, D.; Lee, Y.T.; Liao, W.S.; Yang, C.Y.; Chen, C.H. Electronegative LDL impairs vascular endothelial cell integrity in diabetes by disrupting fibroblast growth factor 2 (FGF2) autoregulation. Diabetes, 2008, 57(1), 158-166.
[77]
Lu, J.; Yang, J.H.; Burns, A.R.; Chen, H.H.; Tang, D.; Walterscheid, J.P.; Suzuki, S.; Yang, C.Y.; Sawamura, T.; Chen, C.H. Mediation of electronegative low-density lipoprotein signaling by LOX-1: A possible mechanism of endothelial apoptosis. Circ. Res., 2009, 104(5), 619-627.
[78]
Chen, C.H.; Ke, L.Y.; Chan, H.C.; Lee, A.S.; Lin, K.D.; Chu, C.S.; Lee, M.Y.; Hsiao, P.J.; Hsu, C.; Chen, C.H.; Shin, S.J. Electronegative low density lipoprotein induces renal apoptosis and fibrosis: STRA6 signaling involved. J. Lipid Res., 2016, 57(8), 1435-1446.
[79]
Revuelta-López, E.; Cal, R.; Julve, J.; Rull, A.; Martínez-Bujidos, M.; Perez-Cuellar, M.; Ordoñez-Llanos, J.; Badimon, L.; Sanchez-Quesada, J.L.; Llorente-Cortés, V. Hypoxia worsens the impact of intracellular triglyceride accumulation promoted by electronegative low-density lipoprotein in cardiomyocytes by impairing perilipin 5 upregulation. Int. J. Biochem. Cell Biol., 2015, 65, 257-267.
[80]
Pedrosa, A.M.; Faine, L.A.; Grosso, D.M.; de Las Heras, B.; Boscá, L.; Abdalla, D.S. Electronegative LDL induction of apoptosis in macrophages: Involvement of Nrf2. Biochim. Biophys. Acta, 2010, 1801(4), 430-437.
[81]
Ursini, F.; Davies, K.J.; Maiorino, M.; Parasassi, T.; Sevanian, A. Atherosclerosis: Another protein misfolding disease? Trends Mol. Med., 2002, 8(8), 370-374.
[82]
Sanchez-Quesada, J.L.; Villegas, S.; Ordonez-Llanos, J.; Electronegative, L.D.L. a link between apoB misfolding, lipoprotein aggregation and proteoglycan binding. Curr. Opin. Lipidol., 2012, 23(5), 479-486.
[83]
Parasassi, T.; Bittolo-Bon, G.; Brunelli, R.; Cazzolato, G.; Krasnowska, E.K.; Mei, G.; Sevanian, A.; Ursini, F. Loss of apoB-100 secondary structure and conformation in hydroperoxide rich, electronegative LDL. Free Radic. Biol. Med., 2001, 31(1), 82-89.
[84]
Parasassi, T.; De Spirito, M.; Mei, G.; Brunelli, R.; Greco, G.; Lenzi, L.; Maulucci, G.; Nicolai, E.; Papi, M.; Arcovito, G.; Tosatto, S.C.; Ursini, F. Low density lipoprotein misfolding and amyloidogenesis. FASEB J., 2008, 22(7), 2350-2356.
[85]
Asatryan, L.; Hamilton, R.T.; Isas, J.M.; Hwang, J.; Kayed, R.; Sevanian, A. LDL phospholipid hydrolysis produces modified electronegative particles with an unfolded apoB-100 protein. J. Lipid Res., 2005, 46(1), 115-122.
[86]
Brunelli, R.; Balogh, G.; Costa, G.; De Spirito, M.; Greco, G.; Mei, G.; Nicolai, E.; Vigh, L.; Ursini, F.; Parasassi, T. Estradiol binding prevents ApoB-100 misfolding in electronegative LDL. Biochemistry, 2010, 49(34), 7297-7302.
[87]
Brunelli, R.; De Spirito, M.; Mei, G.; Papi, M.; Perrone, G.; Stefanutti, C.; Parasassi, T. Misfolding of apoprotein B-100, LDL aggregation and 17-β -estradiol in atherogenesis. Curr. Med. Chem., 2014, 21(20), 2276-2283.
[88]
Oörni, K.; Pentikäinen, M.O.; Ala-Korpela, M.; Kovanen, P.T. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J. Lipid Res., 2000, 41(11), 1703-1714.
[89]
Pentikäinen, M.O.; Hyvönen, M.T.; Oörni, K.; Hevonoja, T.; Korhonen, A.; Lehtonen-Smeds, E.M.; Ala-Korpela, M.; Kovanen, P.T. Altered phospholipid-apoB-100 interactions and generation of extra membrane material in proteolysis-induced fusion of LDL particles. J. Lipid Res., 2001, 42(6), 916-922.
[90]
Pentikäinen, M.O.; Oörni, K.; Ala-Korpela, M.; Kovanen, P.T. Modified LDL - trigger of atherosclerosis and inflammation in the arterial intima. J. Intern. Med., 2000, 247(3), 359-370.
[91]
Oörni, K.; Pentikäinen, M.O.; Annila, A.; Kovanen, P.T. Oxidation of low density lipoprotein particles decreases their ability to bind to human aortic proteoglycans. Dependence on oxidative modification of the lysine residues. J. Biol. Chem., 1997, 272(34), 21303-21311.
[92]
Bancells, C.; Villegas, S.; Blanco, F.J.; Benítez, S.; Gállego, I.; Beloki, L.; Pérez-Cuellar, M.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. Aggregated electronegative low density lipoprotein in human plasma shows a high tendency toward phospholipolysis and particle fusion. J. Biol. Chem., 2010, 285(42), 32425-32435.
[93]
Bancells, C.; Benítez, S.; Villegas, S.; Jorba, O.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. Novel phospholipolytic activities associated with electronegative low-density lipoprotein are involved in increased self-aggregation. Biochemistry, 2008, 47(31), 8186-8194.
[94]
Bancells, C.; Benítez, S.; Jauhiainen, M.; Ordóñez-Llanos, J.; Kovanen, P.T.; Villegas, S.; Sánchez-Quesada, J.L.; Oörni, K. High binding affinity of electronegative LDL to human aortic proteoglycans depends on its aggregation level. J. Lipid Res., 2009, 50(3), 446-455.
[95]
Blanco, F.J.; Villegas, S.; Benítez, S.; Bancells, C.; Diercks, T.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. 2D-NMR reveals different populations of exposed lysine residues in the apoB-100 protein of electronegative and electropositive fractions of LDL particles. J. Lipid Res., 2010, 51(6), 1560-1565.
[96]
Benítez, S.; Bancells, C.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. Pro-inflammatory action of LDL(-) on mononuclear cells is counteracted by increased IL10 production. Biochim. Biophys. Acta, 2007, 1771(5), 613-622.
[97]
Benítez, S.; Sánchez-Quesada, J.L.; Ribas, V.; Jorba, O.; Blanco-Vaca, F.; González-Sastre, F.; Ordóñez-Llanos, J. Platelet-activating factor acetylhydrolase is mainly associated with electronegative low-density lipoprotein subfraction. Circulation, 2003, 108(1), 92-96.
[98]
Sánchez-Quesada, J.L.; Benítez, S.; Pérez, A.; Wagner, A.M.; Rigla, M.; Carreras, G.; Vila, L.; Camacho, M.; Arcelus, R.; Ordóñez-Llanos, J. The inflammatory properties of electronegative low-density lipoprotein from type 1 diabetic patients are related to increased platelet-activating factor acetylhydrolase activity. Diabetologia, 2005, 48(10), 2162-2169.
[99]
Sánchez-Quesada, J.L.; Villegas, S.; Ordóñez-Llanos, J. Electronegative low-density lipoprotein. A link between apolipoprotein B misfolding, lipoprotein aggregation and proteoglycan binding. Curr. Opin. Lipidol., 2012, 23(5), 479-486.
[100]
Rull, A.; Jayaraman, S.; Gantz, D.L.; Rivas-Urbina, A.; Pérez-Cuellar, M.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L.; Gursky, O. Thermal stability of human plasma electronegative low-density lipoprotein: A paradoxical behavior of low-density lipoprotein aggregation. Biochim. Biophys. Acta, 2016, 1861(9 Pt A), 1015-1024.
[101]
Rull, A.; Ordonez-Llanos, J.; Sanchez-Quesada, J.L. The role of LDL-bound apoJ in the development of atherosclerosis. Clin. Lipidol., 2015, 10(4), 321-328.
[102]
Martínez-Bujidos, M.; Rull, A.; González-Cura, B.; Pérez-Cuéllar, M.; Montoliu-Gaya, L.; Villegas, S.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. Clusterin/apolipoprotein J binds to aggregated LDL in human plasma and plays a protective role against LDL aggregation. FASEB J., 2015, 29(5), 1688-1700.
[103]
Demuth, K.; Myara, I.; Chappey, B.; Vedie, B.; Pech-Amsellem, M.A.; Haberland, M.E.; Moatti, N. A cytotoxic electronegative LDL subfraction is present in human plasma. Arterioscler. Thromb. Vasc. Biol., 1996, 16(6), 773-783.
[104]
Sánchez-Quesada, J.L.; Camacho, M.; Antón, R.; Benítez, S.; Vila, L.; Ordóñez-Llanos, J. Electronegative LDL of FH subjects: chemical characterization and induction of chemokine release from human endothelial cells. Atherosclerosis, 2003, 166(2), 261-270.
[105]
Ke, L.Y.; Engler, D.A.; Lu, J.; Matsunami, R.K.; Chan, H.C.; Wang, G.J.; Yang, C.Y.; Chang, J.G.; Chen, C.H. Chemical composition-oriented receptor selectivity of L5, a naturally occurring atherogenic low-density lipoprotein. Pure Appl. Chem., 2011, 83(9)
[http://dx.doi.org/10.1351/PAC-CON-10-12-07]
[106]
Bancells, C.; Canals, F.; Benítez, S.; Colomé, N.; Julve, J.; Ordóñez-Llanos, J.; Sánchez-Quesada, J.L. Proteomic analysis of electronegative low-density lipoprotein. J. Lipid Res., 2010, 51(12), 3508-3515.
[107]
Lee, S.J.; Campos, H.; Moye, L.A.; Sacks, F.M. LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients. Arterioscler. Thromb. Vasc. Biol., 2003, 23(5), 853-858.
[108]
Miller, M. Apolipoprotein C-III: The small protein with sizeable vascular risk. Arterioscler. Thromb. Vasc. Biol., 2017, 37(6), 1013-1014.
[109]
Kawakami, A.; Aikawa, M.; Nitta, N.; Yoshida, M.; Libby, P.; Sacks, F.M. Apolipoprotein CIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G protein- and protein kinase C alpha-mediated nuclear factor-kappaB activation. Arterioscler. Thromb. Vasc. Biol., 2007, 27(1), 219-225.
[110]
Zheng, C.; Azcutia, V.; Aikawa, E.; Figueiredo, J.L.; Croce, K.; Sonoki, H.; Sacks, F.M.; Luscinskas, F.W.; Aikawa, M. Statins suppress apolipoprotein CIII-induced vascular endothelial cell activation and monocyte adhesion. Eur. Heart J., 2013, 34(8), 615-624.
[111]
Kawakami, A.; Aikawa, M.; Alcaide, P.; Luscinskas, F.W.; Libby, P.; Sacks, F.M. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation, 2006, 114(7), 681-687.
[112]
Li, H.; Han, Y.; Qi, R.; Wang, Y.; Zhang, X.; Yu, M.; Tang, Y.; Wang, M.; Shu, Y.N.; Huang, W.; Liu, X.; Rodrigues, B.; Han, M.; Liu, G. Aggravated restenosis and atherogenesis in ApoCIII transgenic mice but lack of protection in ApoCIII knockouts: The effect of authentic triglyceride-rich lipoproteins with and without ApoCIII. Cardiovasc. Res., 2015, 107(4), 579-589.
[113]
Riwanto, M.; Rohrer, L.; Roschitzki, B.; Besler, C.; Mocharla, P.; Mueller, M.; Perisa, D.; Heinrich, K.; Altwegg, L.; von Eckardstein, A.; Lüscher, T.F.; Landmesser, U. Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: Role of high-density lipoprotein-proteome remodeling. Circulation, 2013, 127(8), 891-904.
[114]
Hiukka, A.; Ståhlman, M.; Pettersson, C.; Levin, M.; Adiels, M.; Teneberg, S.; Leinonen, E.S.; Hultén, L.M.; Wiklund, O.; Oresic, M.; Olofsson, S.O.; Taskinen, M.R.; Ekroos, K.; Borén, J. ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan. Diabetes, 2009, 58(9), 2018-2026.
[115]
Morton, R.E.; Gnizak, H.M.; Greene, D.J.; Cho, K.H.; Paromov, V.M. Lipid transfer inhibitor protein (apolipoprotein F) concentration in normolipidemic and hyperlipidemic subjects. J. Lipid Res., 2008, 49(1), 127-135.
[116]
Morton, R.E.; Greene, D.J. CETP and lipid transfer inhibitor protein are uniquely affected by the negative charge density of the lipid and protein domains of LDL. J. Lipid Res., 2003, 44(12), 2287-2296.
[117]
Wyatt, A.; Yerbury, J.; Poon, S.; Dabbs, R.; Wilson, M. Chapter 6: The chaperone action of clusterin and its putative role in quality control of extracellular protein folding. Adv. Cancer Res., 2009, 104, 89-114.
[118]
Rohne, P.; Prochnow, H.; Koch-Brandt, C. The CLU-files: Disentanglement of a mystery. Biomol. Concepts, 2016, 7(1), 1-15.
[119]
Ishikawa, Y.; Ishii, T.; Akasaka, Y.; Masuda, T.; Strong, J.P.; Zieske, A.W.; Takei, H.; Malcom, G.T.; Taniyama, M.; Choi-Miura, N.H.; Tomita, M. Immunolocalization of apolipoproteins in aortic atherosclerosis in American youths and young adults: Findings from the PDAY study. Atherosclerosis, 2001, 158(1), 215-225.
[120]
Foglio, E.; Puddighinu, G.; Fasanaro, P.; D’Arcangelo, D.; Perrone, G.A.; Mocini, D.; Campanella, C.; Coppola, L.; Logozzi, M.; Azzarito, T.; Marzoli, F.; Fais, S.; Pieroni, L.; Marzano, V.; Germani, A.; Capogrossi, M.C.; Russo, M.A.; Limana, F. Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI through epicardial activation, enhanced arteriogenesis and reduced apoptosis. Int. J. Cardiol., 2015, 197, 333-347.
[121]
Schwarz, M.; Spath, L.; Lux, C.A.; Paprotka, K.; Torzewski, M.; Dersch, K.; Koch-Brandt, C.; Husmann, M.; Bhakdi, S. Potential protective role of apoprotein J (clusterin) in atherogenesis: binding to enzymatically modified low-density lipoprotein reduces fatty acid-mediated cytotoxicity. Thromb. Haemost., 2008, 100(1), 110-118.
[122]
Tsukamoto, K.; Mani, D.R.; Shi, J.; Zhang, S.; Haagensen, D.E.; Otsuka, F.; Guan, J.; Smith, J.D.; Weng, W.; Liao, R.; Kolodgie, F.D.; Virmani, R.; Krieger, M. Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease. Proc. Natl. Acad. Sci. USA, 2013, 110(42), 17023-17028.
[123]
Braesch-Andersen, S.; Beckman, L.; Paulie, S.; Kumagai-Braesch, M. ApoD mediates binding of HDL to LDL and to growing T24 carcinoma. PLoS One, 2014, 9(12), e115180.
[124]
Caslake, M.J.; Packard, C.J. Lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase) and cardiovascular disease. Curr. Opin. Lipidol., 2003, 14(4), 347-352.
[125]
Bhatti, S.; Hakeem, A.; Cilingiroglu, M. Lp-PLA(2) as a marker of cardiovascular diseases. Curr. Atheroscler. Rep., 2010, 12(2), 140-144.
[126]
Stafforini, D.M. Biology of platelet-activating factor acetylhydrolase (PAF-AH, lipoprotein associated phospholipase A2). Cardiovasc. Drugs Ther., 2009, 23(1), 73-83.
[127]
Holopainen, J.M.; Medina, O.P.; Metso, A.J.; Kinnunen, P.K. Sphingomyelinase activity associated with human plasma low density lipoprotein. J. Biol. Chem., 2000, 275(22), 16484-16489.
[128]
Kinnunen, P.K.; Holopainen, J.M. Sphingomyelinase activity of LDL: A link between atherosclerosis, ceramide, and apoptosis? Trends Cardiovasc. Med., 2002, 12(1), 37-42.
[129]
Estruch, M.; Sanchez-Quesada, J.L.; Beloki, L.; Ordoñez-Llanos, J.; Benitez, S. The induction of cytokine release in monocytes by electronegative low-density lipoprotein (ldl) is related to its higher ceramide content than native LDL. Int. J. Mol. Sci., 2013, 14(2), 2601-2616.
[130]
Estruch, M.; Sánchez-Quesada, J.L.; Ordóñez-Llanos, J.; Benítez, S. Ceramide-enriched LDL induces cytokine release through TLR4 and CD14 in monocytes. Similarities with electronegative LDL. Clin. Investig. Arterioscler., 2014, 26(3), 131-137.
[131]
Ke, L.Y.; Chan, H.C.; Chen, C.C.; Lu, J.; Marathe, G.K.; Chu, C.S.; Chan, H.C.; Wang, C.Y.; Tung, Y.C.; McIntyre, T.M.; Yen, J.H.; Chen, C.H. Enhanced sphingomyelinase activity contributes to the apoptotic capacity of electronegative low-density lipoprotein. J. Med. Chem., 2016, 59(3), 1032-1040.
[132]
Mackness, M.; Durrington, P.; Mackness, B. Paraoxonase 1 activity, concentration and genotype in cardiovascular disease. Curr. Opin. Lipidol., 2004, 15(4), 399-404.

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