Modified LDL Immune Complexes and Cardiovascular Disease

Author(s): Maria F. Lopes-Virella, Gabriel Virella*

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 9 , 2019

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Modified forms of LDL, both spontaneously formed in the organism or prepared in the laboratory, are immunogenic. As a consequence, antigen-antibody complexes (immune complexes, IC) formed in vivo can be measured in the peripheral blood, and their levels are strong predictors of cardiovascular disease (CVD). It has been possible to generate antibodies that recognize different LDL modifications, allowing the analysis of circulating IC constitution. Clinical studies showed that the antigenic constitution of the IC has a modulating effect on the development of CVD. Patients whose IC react strongly with antibodies to copper oxidized LDL (oxLDL) show progressive development of atherosclerosis as demonstrated by increased intima–media thickness and increased coronary calcification scores. In contrast, patients whose IC react strongly with antibodies to the heavily oxidized malondialdehyde LDL prepared in vitro (MDA-LDL) are at a high risk of acute vascular events, mainly myocardial infarction. In vitro studies have shown that while oxLDL IC induce both cell proliferation and mild to moderate macrophage apoptosis, MDA-LDL IC induce a more marked macrophage apoptosis but not cell proliferation. In addition, MDA-LDL IC induce the release of higher levels of matrix metalloproteinases and TNF than oxLDL IC. High levels of TNF are likely to be a major factor leading to apoptosis and high levels of metalloproteinases are likely to play a role in the thinning of the fibrous cap of the atheromatous plaque. The combination of apoptosis and fibrous cap thinning is a well-known characteristic of vulnerable plaques, which are more prone to rupture and responsible for the majority of acute cardiovascular events.

Keywords: Modified LDL, LDL-immune complexes, MDA-LDL, apoptosis, vascular inflammation, labile plaques, oxLDL.

Miller, Y.I.; Choi, S.H.; Fang, L.; Tsimikas, S. Lipoprotein modification and macrophage uptake: role of pathologic cholesterol transport in atherogenesis. Subcell. Biochem., 2010, 51, 229-251.
Giacco, F.; Brownlee, M. Oxidative stress and diabetic complications. Circ. Res., 2010, 107(9), 1058-1070.
Holvoet, P. Endothelial dysfunction, oxidation of low-density lipoprotein, and cardiovascular disease. Ther. Apher., 1999, 3(4), 287-293.
Parthasarathy, S.; Printz, D.J.; Boyd, D.; Joy, L.; Steinberg, D. Macrophage oxidation of low density lipoprotein generates a modified form recognized by the scavenger receptor. Arteriosclerosis, 1986, 6(5), 505-510.
Silverstein, R.L.; Li, W.; Park, Y.M.; Rahaman, S.O. Mechanisms of cell signaling by the scavenger receptor CD36: implications in atherosclerosis and thrombosis. Trans. Am. Clin. Climatol. Assoc., 2010, 121, 206-220.
Hoff, H.F.; O’Neil, J.; Chisolm, G.M., III; Cole, T.B.; Quehenberger, O.; Esterbauer, H.; Jürgens, G. Modification of low density lipoprotein with 4-hydroxynonenal induces uptake by macrophages. Arteriosclerosis, 1989, 9(4), 538-549.
Fogelman, A.M.; Shechter, I.; Seager, J.; Hokom, M.; Child, J.S.; Edwards, P.A. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc. Natl. Acad. Sci. USA, 1980, 77(4), 2214-2218.
Hessler, J.R.; Morel, D.W.; Lewis, L.J.; Chisolm, G.M. Lipoprotein oxidation and lipoprotein-induced cytotoxicity. Arteriosclerosis, 1983, 3(3), 215-222.
Henriksen, T.; Evensen, S.A.; Carlander, B. Injury to human endothelial cells in culture induced by LDL. Scand. J. Clin. Lab. Invest., 1979, 39, 361-364.
Rajavashisth, T.B.; Andalibi, A.; Territo, M.C. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified LDL. Nature, 1990, 344, 254-257.
Kugiyama, K.; Sakamoto, T.; Musumi, I.; Sugiyama, S.; Ohgushi, M.; Ogawa, H.; Horiguchi, M.; Yasue, H. Transferrable lipids in oxidized LDL stimulate PAI-1 and inhibt TPA release from endothelial cells. Circ. Res., 1993, 73, 335-343.
Lundberg, A.M.; Hansson, G.K. Innate immune signals in atherosclerosis. Clin. Immunol., 2010, 134(1), 5-24.
Andersson, J.; Libby, P.; Hansson, G.K. Adaptive immunity and atherosclerosis. Clin. Immunol., 2010, 134(1), 33-46.
de Boer, O.J.; van der Wal, A.C.; Verhagen, C.E.; Becker, A.E. Cytokine secretion profiles of cloned T cells from human aortic atherosclerotic plaques. J. Pathol., 1999, 188(2), 174-179.
Li, W.; Febbraio, M.; Reddy, S.P.; Yu, D.Y.; Yamamoto, M.; Silverstein, R.L. CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs. J. Clin. Invest., 2010, 120(11), 3996-4006.
Quinn, M.T.; Parthasarathy, S.; Fong, L.G.; Steinberg, D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc. Natl. Acad. Sci. USA, 1987, 84(9), 2995-2998.
Kahn, B.V.; Parthasarathy, S.S.; Alexander, R.W.; Medford, R.M. Modified LDL and its constituents augment cytokine-activated vascular cell adhesion molecule -1 gene expression in human vascular endothelial cells. J. Clin. Invest., 1995, 95, 1262-1270.
Takei, A.; Huang, Y.; Lopes-Virella, M.F. Expression of adhesion molecules by human endothelial cells exposed to oxidized low density lipoprotein. Influences of degree of oxidation and location of oxidized LDL. Atherosclerosis, 2001, 154(1), 79-86.
Frostegård, J.; Nilsson, J.; Haegerstrand, A.; Hamsten, A.; Wigzell, H.; Gidlund, M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937. Proc. Natl. Acad. Sci. USA, 1990, 87(3), 904-908.
Vlassara, H.; Cai, W.; Crandall, J.; Goldberg, T.; Oberstein, R.; Dardaine, V.; Peppa, M.; Rayfield, E.J. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc. Natl. Acad. Sci. USA, 2002, 99(24), 15596-15601.
Wendt, T.; Bucciarelli, L.; Qu, W.; Lu, Y.; Yan, S.F.; Stern, D.M.; Schmidt, A.M. Receptor for advanced glycation endproducts (RAGE) and vascular inflammation: insights into the pathogenesis of macrovascular complications in diabetes. Curr. Atheroscler. Rep., 2002, 4(3), 228-237.
Vlassara, H.; Bucala, R.; Striker, L. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab. Invest., 1994, 70(2), 138-151.
Schmidt, A.M.; Hori, O.; Chen, J.X.; Li, J.F.; Crandall, J.; Zhang, J.; Cao, R.; Yan, S.D.; Brett, J.; Stern, D. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J. Clin. Invest., 1995, 96(3), 1395-1403.
Steinbrecher, U.P.; Fisher, M.; Witztum, J.L.; Curtiss, L.K. Immunogenicity of homologous low density lipoprotein after methylation, ethylation, acetylation, or carbamylation: generation of antibodies specific for derivatized lysine. J. Lipid Res., 1984, 25(10), 1109-1116.
Uchida, K.; Sakai, K.; Itakura, K.; Osawa, T.; Toyokuni, S. Protein modification by lipid peroxidation products: formation of malondialdehyde-derived N(epsilon)-(2-propenol)lysine in proteins. Arch. Biochem. Biophys., 1997, 346(1), 45-52.
Palinski, W.; Ylä-Herttuala, S.; Rosenfeld, M.E.; Butler, S.W.; Socher, S.A.; Parthasarathy, S.; Curtiss, L.K.; Witztum, J.L. Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis, 1990, 10(3), 325-335.
Ylä-Herttuala, S.; Palinski, W.; Butler, S.W.; Picard, S.; Steinberg, D.; Witztum, J.L. Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler. Thromb., 1994, 14(1), 32-40.
Mironova, M.; Virella, G.; Lopes-Virella, M.F. Isolation and characterization of human antioxidized LDL autoantibodies. Arterioscler. Thromb. Vasc. Biol., 1996, 16(2), 222-229.
Virella, G.; Koskinen, S.; Krings, G.; Onorato, J.M.; Thorpe, S.R.; Lopes-Virella, M. Immunochemical characterization of purified human oxidized low-density lipoprotein antibodies. Clin. Immunol., 2000, 95(2), 135-144.
Virella, G.; Thorpe, S.R.; Alderson, N.L.; Derrick, M.B.; Chassereau, C.; Rhett, J.M.; Lopes-Virella, M.F. Definition of the immunogenic forms of modified human LDL recognized by human autoantibodies and by rabbit hyperimmune antibodies. J. Lipid Res., 2004, 45(10), 1859-1867.
Lopes-Virella, M.F.; Virella, G. Pathogenic role of modified LDL antibodies and immune complexes in atherosclerosis. J. Atheroscler. Thromb., 2013, 20(10), 743-754.
Orekhov, A.N.; Tertov, V.V. Antibody-like immunoglobulins G against low density lipoprotein that stimulate lipid accumulation in cultured cells. Adv. Exp. Med. Biol., 1991, 285, 399-404.
Virella, G.; Wilson, K.; Elkes, J.; Hammad, S.M.; Rajab, H.A.; Li, Y.; Chassereau, C.; Huang, Y.; Lopes-Virella, M. Immune complexes containing malondialdehyde (MDA) LDL induce apoptosis in human macrophages. Clin. Immunol., 2018, 187, 1-9.
Orekhov, A.N.; Tertov, V.V.; Kabakov, A.E.; Adamova, I.; Pokrovsky, S.N.; Smirnov, V.N. Autoantibodies against modified low density lipoprotein. Nonlipid factor of blood plasma that stimulates foam cell formation. Arterioscler. Thromb., 1991, 11(2), 316-326.
Virella, G.; Thorpe, S.R.; Alderson, N.L.; Stephan, E.M.; Atchley, D.H.; Wagner, F.; Lopes-Virella, M.F.; Group, D.E.R. Autoimmune response to advanced glycosylation end-products of human low density lipoprotein. J. Lipid Res., 2003, 443, 487-493.
Virella, G.; Lopes-Virella, M.F. Lipoprotein autoantibodies: measurement and significance. Clin. Diagn. Lab. Immunol., 2003, 10(4), 499-505.
Virella, G.; Carter, R.E.; Saad, A.; Crosswell, E.G.; Game, B.A.; Lopes-Virella, M.F. Distribution of IgM and IgG antibodies to oxidized LDL in immune complexes isolated from patients with type 1 diabetes and its relationship with nephropathy. Clin. Immunol., 2008, 127(3), 394-400.
Saad, A.F.; Virella, G.; Chassereau, C.; Boackle, R.J.; Lopes-Virella, M.F. OxLDL immune complexes activate complement and induce cytokine production by MonoMac 6 cells and human macrophages. J. Lipid Res., 2006, 47(9), 1975-1983.
Lopes-Virella, M.F.; Mironova, M.; Virella, G. LDL-containing immune complexes and atherosclerosis in diabetes mellitus. Diabetes Rev. (Alex.), 1997, 58, 410-424.
Lopes-Virella, M.F.; Virella, G.; Orchard, T.J.; Koskinen, S.; Evans, R.W.; Becker, D.J.; Forrest, K.Y. Antibodies to oxidized LDL and LDL-containing immune complexes as risk factors for coronary artery disease in diabetes mellitus. Clin. Immunol., 1999, 90, 165-172.
Mironova, M.A.; Klein, R.L.; Virella, G.T.; Lopes-Virella, M.F. Anti-modified LDL antibodies, LDL-containing immune complexes, and susceptibility of LDL to in vitro oxidation in patients with type 2 diabetes. Diabetes, 2000, 49(6), 1033-1041.
Orekhov, A.N.; Kalenich, O.S.; Tetov, V.V.; Novikov, I.D.; Vorobeva, E.G. Cholesterol level in circulating immune complexes as a marker of coronary atherosclerosis. Adv. Exp. Med. Biol., 1990, 285, 393-397.
Orekhov, A.N.; Kalenich, O.S.; Tertov, V.V.; Novikov, I.D. Lipoprotein immune complexes as markers of atherosclerosis. Int. J. Tissue React., 1991, 13(5), 233-236.
Lopes-Virella, M.F.; McHenry, M.B.; Lipsitz, S.; Yim, E.; Wilson, P.F.; Lackland, D.T.; Lyons, T.; Jenkins, A.J.; Virella, G. Immune complexes containing modified lipoproteins are related to the progression of internal carotid intima-media thickness in patients with type 1 diabetes. Atherosclerosis, 2007, 190(2), 359-369.
Lopes-Virella, M.F.; Baker, N.L.; Hunt, K.J.; Lachin, J.; Nathan, D.; Virella, G. Oxidized LDL immune complexes and coronary artery calcification in type 1 diabetes. Atherosclerosis, 2011, 214(2), 462-467.
Lopes-Virella, M. F.; Hunt, K. J.; Baker, N. L.; Lachin, J.; Nathan, D. M.; Virella, G. Levels of oxidized LDL and advanced glycation end products-modified LDL in circulating immune complexes are strongly associated with increased levels of carotid intima-media thickness and its progression in type 1 diabetes. 2011, 60, 582-589.
Lopes-Virella, M.F.; Hunt, K.J.; Baker, N.L.; Virella, G.; Moritz, T. VADT Investigators. The levels of MDA-LDL in circulating immune complexes predict myocardial infarction in the VADT study. Atherosclerosis, 2012, 224(2), 526-531.
Hernández-Vargas, P.; Ortiz-Muñoz, G.; López-Franco, O.; Suzuki, Y.; Gallego-Delgado, J.; Sanjuán, G.; Lázaro, A.; López-Parra, V.; Ortega, L.; Egido, J.; Gómez-Guerrero, C. Fcgamma receptor deficiency confers protection against atherosclerosis in apolipoprotein E knockout mice. Circ. Res., 2006, 99(11), 1188-1196.
Li, Y.; Lu, Z.; Huang, Y.; Lopes-Virella, M.F.; Virella, G.F. (ab’)2 fragments of anti-oxidized LDL IgG attenuate vascular inflammation and atherogenesis in diabetic LDL receptor-deficient mice. Clin. Immunol., 2016, 173, 50-56.
Mallavia, B.; Oguiza, A.; Lopez-Franco, O.; Recio, C.; Ortiz-Muñoz, G.; Lazaro, I.; Lopez-Parra, V.; Egido, J.; Gomez-Guerrero, C. Gene deficiency in activating Fc gamma receptors influences the macrophage phenotypic balance and reduces atherosclerosis in mice. PLoS One, 2013, 8(6), e66754.
Griffith, R.L.; Virella, G.T.; Stevenson, H.C.; Lopes-Virella, M.F. Low density lipoprotein metabolism by human macrophages activated with low density lipoprotein immune complexes. A possible mechanism of foam cell formation. J. Exp. Med., 1988, 168, 1041-1059.
Kiener, P.A.; Rankin, B.M.; Davis, P.M.; Yocum, S.A.; Warr, G.A.; Grove, R.I. Immune complexes of LDL induce atherogenic responses in human monocytic cells. Arterioscler. Thromb. Vasc. Biol., 1995, 15(7), 990-999.
Klimov, A.N.; Denisenko, A.D.; Popov, A.V.; Nagornev, V.A.; Pleskov, V.M.; Vinogradov, A.G.; Denisenko, T.V.; Magracheva, E.Y.; Kheifes, G.M.; Kuznetzov, A.S. Lipoprotein-antibody immune complexes. Their catabolism and role in foam cell formation. Atherosclerosis, 1985, 58(1-3), 1-15.
Klimov, A.N.; Denisenko, A.D.; Vinogradov, A.G.; Nagornev, V.A.; Pivovarova, Y.I.; Sitnikova, O.D.; Pleskov, V.M. Accumulation of cholesteryl esters in macrophages incubated with human lipoprotein-antibody autoimmune complex. Atherosclerosis, 1988, 74(1-2), 41-46.
Lopes-Virella, M.F.; Griffith, R.L.; Shunk, K.A.; Virella, G.T. Enhanced uptake and impaired intracellular metabolism of low density lipoprotein complexed with anti-low density lipoprotein antibodies. Arterioscler. Thromb., 1991, 11(5), 1356-1367.
Virella, G.; Muñoz, J.F.; Galbraith, G.M.; Gissinger, C.; Chassereau, C.; Lopes-Virella, M.F. Activation of human monocyte-derived macrophages by immune complexes containing low-density lipoprotein. Clin. Immunol. Immunopathol., 1995, 75(2), 179-189.
Virella, G.; Atchley, D.; Koskinen, S.; Zheng, D.; Lopes-Virella, M.F. Proatherogenic and proinflammatory properties of immune complexes prepared with purified human oxLDL antibodies and human oxLDL. Clin. Immunol., 2002, 105(1), 81-92.
Ylä-Herttuala, S. Macrophages and oxidized low density lipoproteins in the pathogenesis of atherosclerosis. Ann. Med., 1991, 23(5), 561-567.
Hörl, G.; Froehlich, H.; Ferstl, U.; Ledinski, G.; Binder, J.; Cvirn, G.; Stojakovic, T.; Trauner, M.; Koidl, C.; Tafeit, E.; Amrein, K.; Scharnagl, H.; Jürgens, G.; Hallström, S. Simvastatin efficiently lowers small LDL-IgG immune complex levels: A therapeutic quality beyond the lipid-lowering effect. PLoS One, 2016, 11(2), e0148210.
Hunt, K.J.; Baker, N.; Cleary, P.; Backlund, J.Y.; Lyons, T.; Jenkins, A.; Virella, G.; Lopes-Virella, M.F. Oxidized LDL and AGE-LDL in circulating immune complexes strongly predict progression of carotid artery IMT in type 1 diabetes. Atherosclerosis, 2013, 231(2), 315-322.
Orekhov, A.N.; Bobryshev, Y.V.; Sobenin, I.A.; Melnichenko, A.A.; Chistiakov, D.A. 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., 2014, 15(7), 12807-12841.
Prasad, A.; Clopton, P.; Ayers, C.; Khera, A.; de Lemos, J.A.; Witztum, J.L.; Tsimikas, S. Relationship of autoantibodies to MDA-LDL and ApoB-immune complexes to sex, ethnicity, subclinical atherosclerosis, and cardiovascular events. Arterioscler. Thromb. Vasc. Biol., 2017, 37(6), 1213-1221.
Sobenin, I.A.; Karagodin, V.P.; Melnichenko, A.C.; Bobryshev, Y.V.; Orekhov, A.N. Diagnostic and prognostic value of low density lipoprotein-containing circulating immune complexes in atherosclerosis. J. Clin. Immunol., 2013, 33(2), 489-495.
Sobenin, I.A.; Salonen, J.T.; Zhelankin, A.V.; Melnichenko, A.A.; Kaikkonen, J.; Bobryshev, Y.V.; Orekhov, A.N. Low density lipoprotein-containing circulating immune complexes: role in atherosclerosis and diagnostic value. BioMed Res. Int., 2014, 2014, 205697.
Virella, G.; Derrick, M.B.; Pate, V.; Chassereau, C.; Thorpe, S.R.; Lopes-Virella, M.F. Development of capture assays for different modifications of human low-density lipoprotein. Clin. Diagn. Lab. Immunol., 2005, 12(1), 68-75.
Virella, G.; Colglazier, J.; Chassereau, C.; Hunt, K.J.; Baker, N.L.; Lopes-Virella, M.F. Immunoassay of modified forms of human low density lipoprotein in isolated circulating immune complexes. J. Immunoassay Immunochem., 2013, 34(1), 61-74.
Libby, P.; Theroux, P. Pathophysiology of coronary artery disease. Circulation, 2005, 111(25), 3481-3488.
Shah, P.K. Pathophysiology of coronary thrombosis: role of plaque rupture and plaque erosion. Prog. Cardiovasc. Dis., 2002, 44(5), 357-368.
Galis, Z.S.; Sukhova, G.K.; Lark, M.W.; Libby, P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest., 1994, 94(6), 2493-2503.
Seimon, T.; Tabas, I. Mechanisms and consequences of macrophage apoptosis in atherosclerosis. J. Lipid Res., 2009, 50(Suppl.), S382-S387.
Virella, G.; Lopes-Virella, M.F. Humoral immunity and atherosclerosis. Nat. Med., 2003, 9(3), 243-244.
Lopes-Virella, M.F.; Binzafar, N.; Rackley, S.; Takei, A.; La Via, M.; Virella, G. The uptake of LDL-IC by human macrophages: predominant involvement of the Fc gamma RI receptor. Atherosclerosis, 1997, 135(2), 161-170.
Shaw, P.X.; Hörkkö, S.; Tsimikas, S.; Chang, M.K.; Palinski, W.; Silverman, G.J.; Chen, P.P.; Witztum, J.L. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler. Thromb. Vasc. Biol., 2001, 21(8), 1333-1339.
Fu, Y.; Huang, Y.; Bandyopadhyay, S.; Virella, G.; Lopes-Virella, M.F. LDL immune complexes stimulate LDL receptor expression in U937 histiocytes via extracellular signal-regulated kinase and AP-1. J. Lipid Res., 2003, 44(7), 1315-1321.
Hammad, S.M.; Twal, W.O.; Barth, J.L.; Smith, K.J.; Saad, A.F.; Virella, G.; Argraves, W.S.; Lopes-Virella, M.F. Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells. Atherosclerosis, 2009, 202(2), 394-404.
Tohyama, Y.; Yamamura, H. Protein tyrosine kinase, syk: a key player in phagocytic cells. J. Biochem., 2009, 145(3), 267-273.
Crowley, M.T.; Costello, P.S.; Fitzer-Attas, C.J.; Turner, M.; Meng, F.; Lowell, C.; Tybulewicz, V.L.; DeFranco, A.L. A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. J. Exp. Med., 1997, 186(7), 1027-1039.
Luo, Y.; Pollard, J.W.; Casadevall, A. Fcgamma receptor cross-linking stimulates cell proliferation of macrophages via the ERK pathway. J. Biol. Chem., 2010, 285(6), 4232-4242.
Huang, Y.; Jaffa, A.; Koskinen, S.; Takei, A.; Lopes-Virella, M.F. Oxidized LDL-containing immune complexes induce Fcgamma receptor I-mediated mitogen-activated protein kinase activation in THP-1 macrophages. Arterioscler. Thromb. Vasc. Biol., 1999, 19(7), 1600-1607.
Oksjoki, R.; Kovanen, P.T.; Lindstedt, K.A.; Jansson, B.; Pentikäinen, M.O. OxLDL-IgG immune complexes induce survival of human monocytes. Arterioscler. Thromb. Vasc. Biol., 2006, 26(3), 576-583.
Datta, S.R.; Brunet, A.; Greenberg, M.E. Cellular survival: a play in three Akts. Genes Dev., 1999, 13(22), 2905-2927.
Al Gadban, M.M.; Smith, K.J.; Soodavar, F.; Piansay, C.; Chassereau, C.; Twal, W.O.; Klein, R.L.; Virella, G.; Lopes-Virella, M.F.; Hammad, S.M. Differential trafficking of oxidized LDL and oxidized LDL immune complexes in macrophages: Impact on oxidative stress. PLoS One, 2010, 5(9), e12534.
Smith, K.J.; Twal, W.O.; Soodavar, F.; Virella, G.; Lopes-Virella, M.F.; Hammad, S.M. Heat shock protein 70B′ (HSP70B′) expression and release in response to human oxidized low density lipoprotein immune complexes in macrophages. J. Biol. Chem., 2010, 285(21), 15985-15993.
de Boer, O.J.; van der Wal, A.C.; Houtkamp, M.A.; Ossewaarde, J.M.; Teeling, P.; Becker, A.E. Unstable atherosclerotic plaques contain T-cells that respond to Chlamydia pneumoniae. Cardiovasc. Res., 2000, 48(3), 402-408.
Lim, W.S.; Timmins, J.M.; Seimon, T.A.; Sadler, A.; Kolodgie, F.D.; Virmani, R.; Tabas, I. Signal transducer and activator of transcription-1 is critical for apoptosis in macrophages subjected to endoplasmic reticulum stress in vitro and in advanced atherosclerotic lesions in vivo. Circulation, 2008, 117(7), 940-951.
Kinscherf, R.; Claus, R.; Wagner, M.; Gehrke, C.; Kamencic, H.; Hou, D.; Nauen, O.; Schmiedt, W.; Kovacs, G.; Pill, J.; Metz, J.; Deigner, H.P. Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent. FASEB J., 1998, 12(6), 461-467.
Hamilton, J.A.; Whitty, G.; Jessup, W. Oxidized LDL can promote human monocyte survival. Arterioscler. Thromb. Vasc. Biol., 2000, 20(10), 2329-2331.
Hundal, R.S.; Gómez-Muñoz, A.; Kong, J.Y.; Salh, B.S.; Marotta, A.; Duronio, V.; Steinbrecher, U.P. Oxidized low density lipoprotein inhibits macrophage apoptosis by blocking ceramide generation, thereby maintaining protein kinase B activation and Bcl-XL levels. J. Biol. Chem., 2003, 278(27), 24399-24408.
Oksjoki, R.; Kovanen, P.T.; Pentikäinen, M.O. Role of complement activation in atherosclerosis. Curr. Opin. Lipidol., 2003, 14(5), 477-482.
Hammad, S.M.; Taha, T.A.; Nareika, A.; Johnson, K.R.; Lopes-Virella, M.F.; Obeid, L.M. Oxidized LDL immune complexes induce release of sphingosine kinase in human U937 monocytic cells. Prostaglandins Other Lipid Mediat., 2006, 79(1-2), 126-140.
Schulze-Osthoff, K.; Ferrari, D.; Los, M.; Wesselborg, S.; Peter, M.E. Apoptosis signaling by death receptors. Eur. J. Biochem., 1998, 254(3), 439-459.
Tsujimoto, Y. Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells, 1998, 3(11), 697-707.
Czabotar, P.E.; Lessene, G.; Strasser, A.; Adams, J.M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol., 2014, 15(1), 49-63.
Hoff, H.F.; Zyromski, N.; Armstrong, D.; O’Neil, J. Aggregation as well as chemical modification of LDL during oxidation is responsible for poor processing in macrophages. J. Lipid Res., 1993, 34(11), 1919-1929.

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Year: 2019
Published on: 21 May, 2019
Page: [1680 - 1692]
Pages: 13
DOI: 10.2174/0929867325666180524114429
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