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Lipoprotein Modification and Macrophage Uptake: Role of Pathologic Cholesterol Transport in Atherogenesis

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Cholesterol Binding and Cholesterol Transport Proteins:

Part of the book series: Subcellular Biochemistry ((SCBI,volume 51))

Abstract

Low-density lipoprotein (LDL) is a major extracellular carrier of cholesterol and, as such, plays important physiologic roles in cellular function and regulation of metabolic pathways. However, under pathologic conditions of hyperlipidemia, oxidative stress and/or genetic disorders, specific components of LDL become oxidized or otherwise modified, and the transport of cholesterol by modified LDL is diverted from its physiologic targets toward excessive cholesterol accumulation in macrophages and the formation of macrophage “foam” cells in the vascular wall. This pathologic deposition of modified lipoproteins and the attendant pro-inflammatory reactions in the artery wall lead to the development of atherosclerotic lesions. Continued accumulation of immunogenic modified lipoproteins and a pro-inflammatory milieu result in the progression of atherosclerotic lesions, which may obstruct the arterial lumen and/or eventually rupture and thrombose, causing myocardial infarction or stroke. In this review, we survey mechanisms of LDL modification and macrophage lipoprotein uptake, including results of recent in vivo experiments, and discuss unresolved problems and controversial issues in this growing field. Future directions in studying foam cell formation may include introducing novel animal models, such as hypercholesterolemic zebrafish, enabling dynamic in vivo observation of macrophage lipid uptake.

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Abbreviations

apoA:

apolipoprotein A

CE:

cholesteryl ester

CAD:

coronary artery disease

FFA:

free fatty acids

Hp:

haptoglobin

Hb:

hemoglobin

HDL:

high density lipoprotein

FH:

familial hypercholesterolemia

LDL:

low density lipoprotein

LDL-C:

LDL cholesterol

LDLR:

LDL receptor

12/15LO:

12/15-lipoxygenase

LRP-1:

LDL receptor related protein-1

LOX-1:

lectin-like oxidized LDL receptor-1

LXR:

liver X receptors

M-CSF:

macrophage colony stimulating factor

MPO:

myeloperoxidase

Nox:

NADPH oxidase

OxLDL:

oxidized LDL

(PRRs):

pattern recognition receptors

PL:

phospholipid

PUFA:

polyunsaturated fatty acids

SR-A:

scavenger receptor type A

RAGE:

receptor for advanced glycation end products

SR-BI:

scavenger receptor type BI

SREC-I:

scavenger receptor expressed by endothelial cells

SR-PSOX/CXCL16:

scavenger receptor for phosphatidylserine and oxidized lipoprotein/chemokine (C-X-C motif) ligand 16

Syk:

spleen tyrosine kinase

VLDL:

very low density lipoprotein

References

  • Asleh, R., Marsh, S., Shilkrut, M., Binah, O., Guetta, J., Lejbkowicz, F., Enav, B., Shehadeh, N., Kanter, Y., Lache, O., Cohen, O., Levy, N.S., and Levy, A.P., 2003, Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ. Res. 92: 1193–1200.

    CAS  PubMed  Google Scholar 

  • Asleh, R., Guetta, J., Kalet-Litman, S., Miller-Lotan, R., and Levy, A.P., 2005, Haptoglobin genotype- and diabetes-dependent differences in iron-mediated oxidative stress in vitro and in vivo. Circ. Res. 96: 435–441.

    CAS  PubMed  Google Scholar 

  • Bae, Y.S., Lee, J.H., Choi, S.H., Kim, S., Almazan, F., Witztum, J.L., and Miller, Y.I., 2009, Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: Toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circ. Res. 104: 210–218.

    CAS  PubMed  Google Scholar 

  • Barry-Lane, P.A., Patterson, C., van der Merwe, M., Hu, Z., Holland, S.M., Yeh, E.T.H., and Runge, M.S., 2001, p47phox is required for atherosclerotic lesion progression in ApoE-/- mice. J. Clin. Invest. 108: 1513–1522.

    CAS  PubMed  Google Scholar 

  • Belkner, J., Stender, H., and Kuhn, H., 1998, The rabbit 15-lipoxygenase preferentially oxygenates LDL cholesterol esters, and this reaction does not require vitamin E. J. Biol. Chem. 273: 23225–23232.

    CAS  PubMed  Google Scholar 

  • Berliner, J.A., Subbanagounder, G., Leitinger, N., Watson, A.D., and Vora, D., 2001, Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc. Med. 11: 142–147.

    CAS  PubMed  Google Scholar 

  • Berliner, J.A., Territo, M.C., Sevanian, A., Ramin, S., Kim, J.A., Bamshad, B., Esterson, M., and Fogelman, A.M., 1990, Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J. Clin. Invest. 85: 1260–1266.

    CAS  PubMed  Google Scholar 

  • Bhakdi, S., Dorweiler, B., Kirchmann, R., Torzewski, J., Weise, E., Tranum-Jensen, J., Walev, I., and Wieland, E., 1995, On the pathogenesis of atherosclerosis: enzymatic transformation of human low density lipoprotein to an atherogenic moiety. J. Exp. Med. 182: 1959–1971.

    CAS  PubMed  Google Scholar 

  • Bostrom, M.A., Boyanovsky, B.B., Jordan, C.T., Wadsworth, M.P., Taatjes, D.J., de Beer, F.C., and Webb, N.R., 2007, Group v secretory phospholipase A2 promotes atherosclerosis: evidence from genetically altered mice. Arterioscler. Thromb. Vasc. Biol. 27: 600–606.

    CAS  PubMed  Google Scholar 

  • Boyanovsky, B.B., Shridas, P., Simons, M., van der Westhuyzen, D.R., and Webb, N.R., 2008, Syndecan-4 mediates macrophage uptake of group V secretory phospholipase A2-modified low density lipoprotein. J. Lipid Res. 50: 641–650.

    PubMed  Google Scholar 

  • Boyanovsky, B.B. and Webb, N.R., 2009, Biology of secretory phospholipase A2. Cardiovasc. Drugs Ther. 23: 61–72.

    CAS  PubMed  Google Scholar 

  • Braun, A., Trigatti, B.L., Post, M.J., Sato, K., Simons, M., Edelberg, J.M., Rosenberg, R.D., Schrenzel, M., and Krieger, M., 2002, Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice. Circ. Res. 90: 270–276.

    CAS  PubMed  Google Scholar 

  • Brennan, M.L., Anderson, M.M., Shih, D.M., Qu, X.D., Wang, X., Mehta, A.C., Lim, L.L., Shi, W., Hazen, S.L., Jacob, J.S., Crowley, J.R., Heinecke, J.W., and Lusis, A.J., 2001, Increased atherosclerosis in myeloperoxidase-deficient mice. J. Clin. Invest. 107: 419–430.

    CAS  PubMed  Google Scholar 

  • Buono, C., Anzinger, J.J., Amar, M., and Kruth, H.S., 2009, Fluorescent pegylated nanoparticles demonstrate fluid-phase pinocytosis by macrophages in mouse atherosclerotic lesions. J. Clin. Invest. 119: 1373–1381.

    CAS  PubMed  Google Scholar 

  • Buono, C., Li, Y., Waldo, S.W., and Kruth, H.S., 2007, Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL. J. Lipid Res. 48: 2411–2418.

    CAS  PubMed  Google Scholar 

  • Burbea, Z., Nakhoul, F., Zoabi, R., Hochberg, I., Levy, N.S., Benchetrit, S., Weissgarten, J., Tovbin, D., Knecht, A., Iaina, A., Herman, M., Kristal, B., and Levy, A.P., 2004, Haptoglobin phenotype as a predictive factor of mortality in diabetic haemodialysis patients. Ann. Clin. Biochem. 41: 469–473.

    CAS  PubMed  Google Scholar 

  • Cathcart, M.K., 2004, Regulation of Superoxide Anion Production by NADPH Oxidase in Monocytes/Macrophages: Contributions to Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 24: 23–28.

    CAS  PubMed  Google Scholar 

  • Choi, S.-H., Harkewicz, R., Lee, J.H., Boullier, A., Almazan, F., Li, A.C., Witztum, J.L., Bae, Y.S., and Miller, Y.I., 2009, Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake. Circ. Res. 104: 1355–1363.

    CAS  PubMed  Google Scholar 

  • Cyrus, T., Pratico, D., Zhao, L., Witztum, J.L., Rader, D.J., Rokach, J., FitzGerald, G.A., and Funk, C.D., 2001, Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice. Circulation 103: 2277–2282.

    CAS  PubMed  Google Scholar 

  • Cyrus, T., Witztum, J.L., Rader, D.J., Tangirala, R., Fazio, S., Linton, M.F., and Funk, C.D., 1999, Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E-deficient mice. J. Clin. Invest. 103: 1597–1604.

    CAS  PubMed  Google Scholar 

  • Daugherty, A., Dunn, J.L., Rateri, D.L., and Heinecke, J.W., 1994, Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J. Clin. Invest. 94: 437–444.

    CAS  PubMed  Google Scholar 

  • Detmers, P.A., Hernandez, M., Mudgett, J., Hassing, H., Burton, C., Mundt, S., Chun, S., Fletcher, D., Card, D.J., Lisnock, J., Weikel, R., Bergstrom, J.D., Shevell, D.E., Hermanowski-Vosatka, A., Sparrow, C.P., Chao, Y.S., Rader, D.J., Wright, S.D., and Pure, E., 2000, Deficiency in inducible nitric oxide synthase results in reduced atherosclerosis in apolipoprotein E-deficient mice. J. Immunol. 165: 3430–3435.

    CAS  PubMed  Google Scholar 

  • Devlin, C.M., Leventhal, A.R., Kuriakose, G., Schuchman, E.H., Williams, K.J., and Tabas, I., 2008, Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression. Arterioscler. Thromb. Vasc. Biol. 28: 1723–1730.

    CAS  PubMed  Google Scholar 

  • Esterbauer, H., Gebicki, J., Puhl, H., and Jurgens, G., 1992, The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic. Biol. Med. 13: 341–390.

    CAS  PubMed  Google Scholar 

  • Esterbauer, H., Jurgens, G., Quehenberger, O., and Koller, E., 1987, Autoxidation of human low density lipoprotein: loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes. J. Lipid Res. 28: 495–509.

    CAS  PubMed  Google Scholar 

  • Ezaki, M., Witztum, J.L., and Steinberg, D., 1995, Lipoperoxides in LDL incubated with fibroblasts that overexpress 15-lipoxygenase. J. Lipid Res. 36: 1996–2004.

    CAS  PubMed  Google Scholar 

  • Febbraio, M., Podrez, E.A., Smith, J.D., Hajjar, D.P., Hazen, S.L., Hoff, H.F., Sharma, K., and Silverstein, R.L., 2000, Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Invest. 105: 1049–1056.

    CAS  PubMed  Google Scholar 

  • Fenske, D., Dersch, K., Lux, C., Zipse, L., Suriyaphol, P., Dragneva, Y., Han, S.R., Bhakdi, S., and Husmann, M., 2008, Enzymatically hydrolyzed low-density lipoprotein modulates inflammatory responses in endothelial cells. Thromb. Haemost. 100: 1146–1154.

    CAS  PubMed  Google Scholar 

  • George, J., Afek, A., Shaish, A., Levkovitz, H., Bloom, N., Cyrus, T., Zhao, L., Funk, C.D., Sigal, E., and Harats, D., 2001, 12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice. Circulation 104: 1646–1650.

    CAS  PubMed  Google Scholar 

  • Glass, C.K. and Witztum, J.L., 2001, Atherosclerosis. The road ahead. Cell 104: 503–516.

    CAS  PubMed  Google Scholar 

  • Goldstein, J.L., Ho, Y.K., Basu, S.K., and Brown, M.S., 1979, Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc. Natl. Acad. Sci. USA 76: 333–337.

    CAS  PubMed  Google Scholar 

  • Goldstein, J.L., Kita, T., and Brown, M.S., 1983, Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. N. Engl. J. Med. 309: 288–296.

    CAS  PubMed  Google Scholar 

  • Harkewicz, R., Hartvigsen, K., Almazan, F., Dennis, E.A., Witztum, J.L., and Miller, Y.I., 2008, Cholesteryl ester hydroperoxides are biologically active components of minimally oxidized LDL. J. Biol. Chem. 283: 10241–10251.

    CAS  PubMed  Google Scholar 

  • Hartvigsen, K., Chou, M.Y., Hansen, L.F., Shaw, P.X., Tsimikas, S., Binder, C.J., and Witztum, J.L., 2009, The role of innate immunity in atherogenesis. J. Lipid Res. 50: S388–S393.

    PubMed  Google Scholar 

  • Horton, J.D., Cohen, J.C., and Hobbs, H.H., 2009, PCSK9: A convertase that coordinates LDL catabolism. J. Lipid Res. 50: S172–S177.

    PubMed  Google Scholar 

  • Hsich, E., Segal, B.H., Pagano, P.J., Rey, F.E., Paigen, B., Deleonardis, J., Hoyt, R.F., Holland, S.M., and Finkel, T., 2000, Vascular effects following homozygous disruption of p47phox : An essential component of NADPH oxidase. Circulation 101: 1234–1236.

    CAS  PubMed  Google Scholar 

  • Huby, T., Doucet, C., Dachet, C., Ouzilleau, B., Ueda, Y., Afzal, V., Rubin, E., Chapman, M.J., and Lesnik, P., 2006, Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues. J. Clin. Invest. 116: 2767–2776.

    CAS  PubMed  Google Scholar 

  • Huo, Y., Zhao, L., Hyman, M.C., Shashkin, P., Harry, B.L., Burcin, T., Forlow, S.B., Stark, M.A., Smith, D.F., Clarke, S., Srinivasan, S., Hedrick, C.C., Pratico, D., Witztum, J.L., Nadler, J.L., Funk, C.D., and Ley, K., 2004, Critical role of macrophage 12/15-lipoxygenase for atherosclerosis in apolipoprotein E-deficient mice. Circulation 110: 2024–2031.

    CAS  PubMed  Google Scholar 

  • Ihrig, M., Dangler, C.A., and Fox, J.G., 2001, Mice lacking inducible nitric oxide synthase develop spontaneous hypercholesterolaemia and aortic atheromas. Atherosclerosis 156: 103–107.

    CAS  PubMed  Google Scholar 

  • Ivandic, B., Castellani, L.W., Wang, X.P., Qiao, J.H., Mehrabian, M., Navab, M., Fogelman, A.M., Grass, D.S., Swanson, M.E., De Beer, M.C., de Beer, F., and Lusis, A.J., 1999, Role of group II secretory phospholipase A2 in atherosclerosis : 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIa phospholipase A2. Arterioscler. Thromb. Vasc. Biol. 19: 1284–1290.

    CAS  PubMed  Google Scholar 

  • Jones, N.L., Reagan, J.W., and Willingham, M.C., 2000, The pathogenesis of foam cell formation: Modified LDL stimulates uptake of co-incubated LDL via macropinocytosis. Arterioscler. Thromb. Vasc. Biol. 20: 773–781.

    CAS  PubMed  Google Scholar 

  • Khoo, J.C., Miller, E., McLoughlin, P., and Steinberg, D., 1988, Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis 8: 348–358.

    CAS  PubMed  Google Scholar 

  • Kirk, E.A., Dinauer, M.C., Rosen, H., Chait, A., Heinecke, J.W., and LeBoeuf, R.C., 2000, Impaired superoxide production due to a deficiency in phagocyte NADPH oxidase fails to inhibit atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 20: 1529–1535.

    CAS  PubMed  Google Scholar 

  • Kodama, T., Freeman, M., Rohrer, L., Zabrecky, J., Matsudaira, P., and Krieger, M., 1990, Type I macrophage scavenger receptor contains alpha-helical and collagen-like coiled coils. Nature 343: 531–535.

    CAS  PubMed  Google Scholar 

  • Kruth, H.S., 2002, Sequestration of aggregated low-density lipoproteins by macrophages. Curr. Opin. Lipidol. 13: 483–488.

    CAS  PubMed  Google Scholar 

  • Kruth, H.S., Jones, N.L., Huang, W., Zhao, B., Ishii, I., Chang, J., Combs, C.A., Malide, D., and Zhang, W.Y., 2005, Macropinocytosis is the endocytic pathway that mediates macrophage foam cell formation with native low density lipoprotein. J. Biol. Chem. 280: 2352–2360.

    CAS  PubMed  Google Scholar 

  • Kuchibhotla, S., Vanegas, D., Kennedy, D.J., Guy, E., Nimako, G., Morton, R.E., and Febbraio, M., 2008, Absence of CD36 protects against atherosclerosis in ApoE knock-out mice with no additional protection provided by absence of scavenger receptor A I/II. Cardiovasc. Res. 78: 185–196.

    CAS  PubMed  Google Scholar 

  • Kunjathoor, V.V., Febbraio, M., Podrez, E.A., Moore, K.J., Andersson, L., Koehn, S., Rhee, J.S., Silverstein, R., Hoff, H.F., and Freeman, M.W., 2002, Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J. Biol. Chem. 277: 49982–49988.

    CAS  PubMed  Google Scholar 

  • Leitinger, N., 2003, Cholesteryl ester oxidation products in atherosclerosis. Mol. Aspects Med. 24: 239–250.

    CAS  PubMed  Google Scholar 

  • Letters, J.M., Witting, P.K., Christison, J.K., Eriksson, A.W., Pettersson, K., and Stocker, R., 1999, Time-dependent changes to lipids and antioxidants in plasma and aortas of apolipoprotein E knockout mice. J. Lipid Res. 40: 1104–1112.

    CAS  PubMed  Google Scholar 

  • Levy, A.P., Hochberg, I., Jablonski, K., Resnick, H.E., Lee, E.T., Best, L., and Howard, B.V., 2002, Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The strong heart study. J. Am. Coll. Cardiol. 40: 1984–1990.

    PubMed  Google Scholar 

  • Levy, A.P., Levy, J.E., Kalet-Litman, S., Miller-Lotan, R., Levy, N.S., Asaf, R., Guetta, J., Yang, C., Purushothaman, K.R., Fuster, V., and Moreno, P.R., 2007, Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler. Thromb. Vasc. Biol. 27: 134–140.

    CAS  PubMed  Google Scholar 

  • Liao, F., Andalibi, A., Qiao, J.H., Allayee, H., Fogelman, A.M., and Lusis, A.J., 1994, Genetic evidence for a common pathway mediating oxidative stress, inflammatory gene induction, and aortic fatty streak formation in mice. J. Clin. Invest. 94: 877–884.

    CAS  PubMed  Google Scholar 

  • Liavonchanka, A. and Feussner, I., 2006, Lipoxygenases: Occurrence, functions and catalysis. J. Plant Physiol. 163: 348–357.

    CAS  PubMed  Google Scholar 

  • Llorente-Cortes, V., Otero-Vinas, M., Camino-Lopez, S., Costales, P., and Badimon, L., 2006, Cholesteryl esters of aggregated LDL are internalized by selective uptake in human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 26: 117–123.

    CAS  PubMed  Google Scholar 

  • Llorente-Cortes, V., Royo, T., Juan-Babot, O., and Badimon, L., 2007, Adipocyte differentiation-related protein is induced by LRP1-mediated aggregated LDL internalization in human vascular smooth muscle cells and macrophages. J. Lipid Res. 48: 2133–2140.

    CAS  PubMed  Google Scholar 

  • Manning-Tobin, J.J., Moore, K.J., Seimon, T.A., Bell, S.A., Sharuk, M., varez-Leite, J.I., de Winther, M.P.J., Tabas, I., and Freeman, M.W., 2009, Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice. Arterioscler. Thromb. Vasc. Biol. 29: 19–26.

    CAS  PubMed  Google Scholar 

  • McMillen, T.S., Heinecke, J.W., and LeBoeuf, R.C., 2005, Expression of human myeloperoxidase by macrophages promotes atherosclerosis in mice. Circulation 111: 2798–2804.

    CAS  PubMed  Google Scholar 

  • Merched, A.J., Ko, K., Gotlinger, K.H., Serhan, C.N., and Chan, L., 2008, Atherosclerosis: Evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 22: 3595–3606.

    CAS  PubMed  Google Scholar 

  • Miller, Y.I., Altamentova, S.M., and Shaklai, N., 1997, Oxidation of low-density lipoprotein by hemoglobin stems from a heme-initiated globin radical: antioxidant role of haptoglobin 248. Biochemistry 36: 12189–12198.

    CAS  PubMed  Google Scholar 

  • Miller, Y.I., Chang, M.K., Binder, C.J., Shaw, P.X., and Witztum, J.L., 2003a, Oxidized low density lipoprotein and innate immune receptors. Curr. Opin. Lipidol. 14: 437–445.

    CAS  PubMed  Google Scholar 

  • Miller, Y.I., Chang, M.K., Funk, C.D., Feramisco, J.R., and Witztum, J.L., 2001, 12/15-Lipoxygenase translocation enhances site-specific actin polymerization in macrophages phagocytosing apoptotic cells. J. Biol. Chem. 276: 19431–19439.

    CAS  PubMed  Google Scholar 

  • Miller, Y.I., Felikman, Y., and Shaklai, N., 1995, The involvement of low-density lipoprotein in hemin transport potentiates peroxidative damage. Biochim. Biophys. Acta 1272: 119–127.

    PubMed  Google Scholar 

  • Miller, Y.I., Felikman, Y., and Shaklai, N., 1996, Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. Arch. Biochem. Biophys. 326: 252–260.

    CAS  PubMed  Google Scholar 

  • Miller, Y.I. and Shaklai, N., 1999, Kinetics of hemin distribution in plasma reveals its role in lipoprotein oxidation. Biochim. Biophys. Acta 1454: 153–164.

    CAS  PubMed  Google Scholar 

  • Miller, Y.I., Viriyakosol, S., Binder, C.J., Feramisco, J.R., Kirkland, T.N., and Witztum, J.L., 2003b, Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J. Biol. Chem. 278: 1561–1568.

    CAS  PubMed  Google Scholar 

  • Miller, Y.I., Viriyakosol, S., Worrall, D.S., Boullier, A., Butler, S., and Witztum, J.L., 2005, Toll-like receptor 4-dependent and -independent cytokine secretion induced by minimally oxidized low-density lipoprotein in macrophages. Arterioscler. Thromb. Vasc. Biol. 25: 1213–1219.

    CAS  PubMed  Google Scholar 

  • Milman, U., Blum, S., Shapira, C., Aronson, D., Miller-Lotan, R., Anbinder, Y., Alshiek, J., Bennett, L., Kostenko, M., Landau, M., Keidar, S., Levy, Y., Khemlin, A., Radan, A., and Levy, A.P., 2008, Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial. Arterioscler. Thromb. Vasc. Biol. 28: 341–347.

    CAS  PubMed  Google Scholar 

  • Moore, K.J., El Khoury, J., Medeiros, L.A., Terada, K., Geula, C., Luster, A.D., and Freeman, M.W., 2002, A CD36-initiated signaling cascade mediates inflammatory effects of beta-amyloid. J. Biol. Chem. 277: 47373–47379.

    CAS  PubMed  Google Scholar 

  • Moore, K.J., Kunjathoor, V.V., Koehn, S.L., Manning, J.J., Tseng, A.A., Silver, J.M., McKee, M., and Freeman, M.W., 2005, Loss of receptor-mediated lipid uptake via scavenger receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J. Clin. Invest. 115: 2192–2201.

    CAS  PubMed  Google Scholar 

  • Moreno, P.R., Purushothaman, K.R., Purushothaman, M., Muntner, P., Levy, N.S., Fuster, V., Fallon, J.T., Lento, P.A., Winterstern, A., and Levy, A.P., 2008, Haptoglobin genotype is a major determinant of the amount of iron in the human atherosclerotic plaque. J. Am. Coll. Cardiol. 52: 1049–1051.

    CAS  PubMed  Google Scholar 

  • Navab, M., Berliner, J.A., Watson, A.D., Hama, S., Territo, M.C., Lusis, A.J., Shih, D.M., Van Lenten, B.J., Frank, J.S., Demer, L.L., Edwards, P.A., and Fogelman, A.M., 1996, The Yin and Yang of oxidation in the development of the fatty streak. Arterioscler. Thromb. Vasc. Biol. 16: 831–842.

    CAS  PubMed  Google Scholar 

  • Nicholls, S.J., Zheng, L., and Hazen, S.L., 2005, Formation of dysfunctional high-density lipoprotein by myeloperoxidase. Trends Cardiovasc. Med. 15: 212–219.

    CAS  PubMed  Google Scholar 

  • Oorni, K., Pentikainen, M.O., Ala-Korpela, M., and Kovanen, P.T., 2000, Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: Molecular mechanisms and effects on matrix interactions. J. Lipid Res. 41: 1703–1714.

    CAS  PubMed  Google Scholar 

  • Park, Y.M., Febbraio, M., and Silverstein, R.L., 2009, CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J. Clin Invest. 119: 136–145.

    CAS  PubMed  Google Scholar 

  • Podrez, E.A., Byzova, T.V., Febbraio, M., Salomon, R.G., Ma, Y., Valiyaveettil, M., Poliakov, E., Sun, M., Finton, P.J., Curtis, B.R., Chen, J., Zhang, R., Silverstein, R.L., and Hazen, S.L., 2007, Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat. Med. 13: 1086–1095.

    CAS  PubMed  Google Scholar 

  • Podrez, E.A., Febbraio, M., Sheibani, N., Schmitt, D., Silverstein, R.L., Hajjar, D.P., Cohen, P.A., Frazier, W.A., Hoff, H.F., and Hazen, S.L., 2000, Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J. Clin. Invest. 105: 1095–1108.

    CAS  PubMed  Google Scholar 

  • Poeckel, D., Zemski Berry, K.A., Murphy, R.C., and Funk, C.D., 2009, Dual 12/15- and 5-lipoxygenase deficiency in macrophages alters arachidonic acid metabolism and attenuates peritonitis and atherosclerosis in APOE knockout mice. J. Biol. Chem. 284: 21077–21089.

    CAS  PubMed  Google Scholar 

  • Qiao, J.H., Tripathi, J., Mishra, N.K., Cai, Y., Tripathi, S., Wang, X.P., Imes, S., Fishbein, M.C., Clinton, S.K., Libby, P., Lusis, A.J., and Rajavashisth, T.B., 1997, Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am. J. Pathol. 150: 1687–1699.

    CAS  PubMed  Google Scholar 

  • Rahaman, S.O., Lennon, D.J., Febbraio, M., Podrez, E.A., Hazen, S.L., and Silverstein, R.L., 2006, A CD36-dependent signaling cascade is necessary for macrophage foam cell formation. Cell Metab. 4: 211–221.

    CAS  PubMed  Google Scholar 

  • Reaven, P., Parthasarathy, S., Grasse, B.J., Miller, E., Steinberg, D., and Witztum, J.L., 1993, Effects of oleate-rich and linoleate-rich diets on the susceptibility of low density lipoprotein to oxidative modification in mildly hypercholesterolemic subjects. J. Clin. Invest. 91: 668–676.

    CAS  PubMed  Google Scholar 

  • Reilly, K.B., Srinivasan, S., Hatley, M.E., Patricia, M.K., Lannigan, J., Bolick, D.T., Vandenhoff, G., Pei, H., Natarajan, R., Nadler, J.L., and Hedrick, C.C., 2004, 12/15-Lipoxygenase activity mediates inflammatory monocyte/endothelial interactions and atherosclerosis in vivo. J. Biol. Chem. 279: 9440–9450.

    CAS  PubMed  Google Scholar 

  • Roguin, A., Koch, W., Kastrati, A., Aronson, D., Schomig, A., and Levy, A.P., 2003, Haptoglobin genotype is predictive of major adverse cardiac events in the 1-year period after percutaneous transluminal coronary angioplasty in individuals with diabetes. Diabetes Care 26: 2628–2631.

    PubMed  Google Scholar 

  • Sakaguchi, H., Takeya, M., Suzuki, H., Hakamata, H., Kodama, T., Horiuchi, S., Gordon, S., van der Laan, L.J., Kraal, G., Ishibashi, S., Kitamura, N., and Takahashi, K., 1998, Role of macrophage scavenger receptors in diet-induced atherosclerosis in mice. Lab. Invest. 78: 423–434.

    CAS  PubMed  Google Scholar 

  • Sakr, S.W., Eddy, R.J., Barth, H., Wang, F., Greenberg, S., Maxfield, F.R., and Tabas, I., 2001, The uptake and degradation of matrix-bound lipoproteins by macrophages require an intact actin cytoskeleton, Rho family GTPases, and myosin ATPase activity. J. Biol. Chem. 276: 37649–37658.

    CAS  PubMed  Google Scholar 

  • Seimon, T.A., Obstfeld, A., Moore, K.J., Golenbock, D.T., and Tabas, I., 2006, Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages. Proc. Natl. Acad. Sci. USA 103: 19794–19799.

    CAS  PubMed  Google Scholar 

  • Sevanian, A. and Asatryan, L., 2002, LDL modification during hemodialysis. Markers for oxidative stress. Contrib. Nephrol. 386–395.

    Google Scholar 

  • Shao, B., Oda, M.N., Bergt, C., Fu, X., Green, P.S., Brot, N., Oram, J.F., and Heinecke, J.W., 2006, Myeloperoxidase impairs ABCA1-dependent cholesterol efflux through methionine oxidation and site-specific tyrosine chlorination of apolipoprotein A-I. J. Biol. Chem. 281: 9001–9004.

    CAS  PubMed  Google Scholar 

  • Shen, J., Herderick, E., Cornhill, J.F., Zsigmond, E., Kim, H.S., Kuhn, H., Guevara, N.V., and Chan, L., 1996, Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J. Clin. Invest. 98: 2201–2208.

    CAS  PubMed  Google Scholar 

  • Shi, W., Wang, X., Shih, D.M., Laubach, V.E., Navab, M., and Lusis, A.J., 2002, Paradoxical reduction of fatty streak formation in mice lacking endothelial nitric oxide synthase. Circulation 105: 2078–2082.

    CAS  PubMed  Google Scholar 

  • Sigari, F., Lee, C., Witztum, J.L., and Reaven, P.D., 1997, Fibroblasts that overexpress 15-lipoxygenase generate bioactive and minimally modified LDL. Arterioscler. Thromb. Vasc. Biol. 17: 3639–3645.

    CAS  PubMed  Google Scholar 

  • Steinberg, D., Glass, C.K., and Witztum, J.L., 2008, Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation 118: 672–677.

    PubMed  Google Scholar 

  • Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C., and Witztum, J.L., 1989, Beyond cholesterol: Modifications of low-density lipoprotein that Increase its atherogenicity. New Engl. J. Med. 320: 915–924.

    CAS  PubMed  Google Scholar 

  • Steinbrecher, U.P., Parthasarathy, S., Leake, D.S., Witztum, J.L., and Steinberg, D., 1984, Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc. Natl. Acad. Sci. USA 81: 3883–3887.

    CAS  PubMed  Google Scholar 

  • Stoletov, K., Fang, L., Choi, S.H., Hartvigsen, K., Hansen, L.F., Hall, C., Pattison, J., Juliano, J., Miller, E.R., Almazan, F., Crosier, P., Witztum, J.L., Klemke, R.L., and Miller, Y.I., 2009, Vascular lipid accumulation, lipoprotein oxidation, and macrophage lipid uptake in hypercholesterolemic zebrafish. Circ. Res. 104: 952–960.

    CAS  PubMed  Google Scholar 

  • Suzuki, H., Kurihara, Y., Takeya, M., Kamada, N., Kataoka, M., Jishage, K., Ueda, O., Sakaguchi, H., Higashi, T., Suzuki, T., Takashima, Y., Kawabe, Y., Cynshi, O., Wada, Y., Honda, M., Kurihara, H., Aburatani, H., Doi, T., Matsumoto, A., Azuma, S., Noda, T., Toyoda, Y., Itakura, H., Yazaki, Y., and Kodama, T., 1997, A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 386: 292–296.

    CAS  PubMed  Google Scholar 

  • Tabas, I., Williams, K.J., and Boren, J., 2007, Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116: 1832–1844.

    CAS  PubMed  Google Scholar 

  • Takahashi, Y., Zhu, H., Xu, W., Murakami, T., Iwasaki, T., Hattori, H., and Yoshimoto, T., 2005, Selective uptake and efflux of cholesteryl linoleate in LDL by macrophages expressing 12/15-lipoxygenase. Biochem. Biophys. Res. Commun. 338: 128–135.

    CAS  PubMed  Google Scholar 

  • Torzewski, M., Suriyaphol, P., Paprotka, K., Spath, L., Ochsenhirt, V., Schmitt, A., Han, S.R., Husmann, M., Gerl, V.B., Bhakdi, S., and Lackner, K.J., 2004, Enzymatic modification of low-density lipoprotein in the arterial wall: A new role for plasmin and matrix metalloproteinases in atherogenesis. Arterioscler. Thromb. Vasc. Biol. 24: 2130–2136.

    CAS  PubMed  Google Scholar 

  • Upston, J.M., Niu, X., Brown, A.J., Mashima, R., Wang, H., Senthilmohan, R., Kettle, A.J., Dean, R.T., and Stocker, R., 2002, Disease stage-dependent accumulation of lipid and protein oxidation products in human atherosclerosis. Am. J. Pathol. 160: 701–710.

    CAS  PubMed  Google Scholar 

  • Virella, G. and Lopes-Virella, M.F., 2008, Atherogenesis and the humoral immune response to modified lipoproteins. Atherosclerosis 200: 239–246.

    CAS  PubMed  Google Scholar 

  • Wang, Z., Nicholls, S.J., Rodriguez, E.R., Kummu, O., Horkko, S., Barnard, J., Reynolds, W.F., Topol, E.J., DiDonato, J.A., and Hazen, S.L., 2007, Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat. Med. 13: 1176–1184.

    CAS  PubMed  Google Scholar 

  • Webb, N.R. and Moore, K.J., 2007, Macrophage-derived foam cells in atherosclerosis: Lessons from murine models and implications for therapy. Curr. Drug Targets 8: 1249–1263.

    CAS  PubMed  Google Scholar 

  • Witztum, J.L., 2005, You are right too! J Clin Invest 115: 2072–2075.

    CAS  PubMed  Google Scholar 

  • Yamamoto, S., 1992, Mammalian lipoxygenases: Molecular structures and functions. Biochim. Biophys. Acta 1128: 117–131.

    CAS  PubMed  Google Scholar 

  • Yamashita, S., Hirano, K., Kuwasako, T., Janabi, M., Toyama, Y., Ishigami, M., and Sakai, N., 2007, Physiological and pathological roles of a multi-ligand receptor CD36 in atherogenesis; insights from CD36-deficient patients. Mol. Cell. Biochem. 299: 19–22.

    CAS  PubMed  Google Scholar 

  • Zhao, B., Li, Y., Buono, C., Waldo, S.W., Jones, N.L., Mori, M., and Kruth, H.S., 2006, Constitutive receptor-independent low density lipoprotein uptake and cholesterol accumulation by macrophages differentiated from human monocytes with macrophage-colony-stimulating factor (M-CSF). J. Biol. Chem. 281: 15757–15762.

    CAS  PubMed  Google Scholar 

  • Zhu, H., Takahashi, Y., Xu, W., Kawajiri, H., Murakami, T., Yamamoto, M., Iseki, S., Iwasaki, T., Hattori, H., and Yoshimoto, T., 2003, Low density lipoprotein receptor-related protein-mediated membrane translocation of 12/15-lipoxygenase is required for oxidation of low density lipoprotein by macrophages. J. Biol. Chem. 278: 13350–13355.

    CAS  PubMed  Google Scholar 

  • Ziouzenkova, O., Asatryan, L., Akmal, M., Tetta, C., Wratten, M.L., Loseto-Wich, G., Jurgens, G., Heinecke, J., and Sevanian, A., 1999, Oxidative cross-linking of ApoB100 and hemoglobin results in low density lipoprotein modification in blood. Relevance to atherogenesis caused by hemodialysis. J. Biol. Chem. 274: 18916–18924.

    CAS  PubMed  Google Scholar 

  • Ziouzenkova, O., Asatryan, L., Tetta, C., Wratten, M.L., Hwang, J., and Sevanian, A., 2002, Oxidative stress during ex vivo hemodialysis of blood is decreased by a novel hemolipodialysis procedure utilizing antioxidants. Free Radic. Biol. Med. 33: 248–258.

    CAS  PubMed  Google Scholar 

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Acknowledgments:

Work described in this review contributed by the authors was supported by NIH grants HL081862 and GM069338 (Y.I.M.), and a grant from the Leducq Fondation (Y.I.M. and S.T.).

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  1. Department of Medicine, University of California, San Diego, La Jolla, CA, 92037-0682, USA

    Yury I. Miller, Soo-Ho Choi, Longhou Fang & Sotirios Tsimikas

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    J. Robin Harris

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Miller, Y.I., Choi, SH., Fang, L., Tsimikas, S. (2010). Lipoprotein Modification and Macrophage Uptake: Role of Pathologic Cholesterol Transport in Atherogenesis. In: Harris, J. (eds) Cholesterol Binding and Cholesterol Transport Proteins:. Subcellular Biochemistry, vol 51. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-8622-8_8

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