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Subendothelial retention of atherogenic lipoproteins in early atherosclerosis

Naturevolume 417pages750754 (2002) | Download Citation

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Abstract

Complications of atherosclerosis are the most common cause of death in Western societies1. Among the many risk factors identified by epidemiological studies, only elevated levels of lipoproteins containing apolipoprotein (apo) B can drive the development of atherosclerosis in humans and experimental animals even in the absence of other risk factors2. However, the mechanisms that lead to atherosclerosis are still poorly understood. We tested the hypothesis that the subendothelial retention of atherogenic apoB-containing lipoproteins is the initiating event in atherogenesis3. The extracellular matrix of the subendothelium, particularly proteoglycans, is thought to play a major role in the retention of atherogenic lipoproteins4. The interaction between atherogenic lipoproteins and proteoglycans involves an ionic interaction between basic amino acids in apoB100 and negatively charged sulphate groups on the proteoglycans5. Here we present direct experimental evidence that the atherogenicity of apoB-containing low-density lipoproteins (LDL) is linked to their affinity for artery wall proteoglycans. Mice expressing proteoglycan-binding-defective LDL developed significantly less atherosclerosis than mice expressing wild-type control LDL. We conclude that subendothelial retention of apoB100-containing lipoprotein is an early step in atherogenesis.

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References

  1. 1

    Ross, R. Cell biology of atherosclerosis. Annu. Rev. Physiol. 57, 791–804 (1995)

  2. 2

    Glass, C. K. & Witztum, J. L. Atherosclerosis. The Road Ahead. Cell 104, 503–516 (2001)

  3. 3

    Williams, K. J. & Tabas, I. The response-to-retention hypothesis of early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 15, 551–561 (1995)

  4. 4

    Srinivasan, S. R. et al. Low density lipoprotein retention by aortic tissue. Contribution of extracellular matrix. Atherosclerosis 62, 201–208 (1986)

  5. 5

    Boren, J. et al. Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding. J. Clin. Invest. 101, 2658–2664 (1998)

  6. 6

    Boren, J. et al. Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J. Clin. Invest. 101, 1084–1093 (1998)

  7. 7

    Weisgraber, K. H. & Rall, S. C. Jr Human apolipoprotein B-100 heparin-binding sites. J. Biol. Chem. 262, 11097–11103 (1987)

  8. 8

    Hirose, N., Blankenship, D. T., Krivanek, M. A., Jackson, R. L. & Cardin, A. D. Isolation and characterization of four heparin-binding cyanogen bromide peptides of human plasma apolipoprotein B. Biochemistry 26, 5505–5512 (1987)

  9. 9

    Camejo, G., Olofsson, S. O., Lopez, F., Carlsson, P. & Bondjers, G. Identification of Apo B-100 segments mediating the interaction of low density lipoproteins with arterial proteoglycans. Arteriosclerosis 8, 368–377 (1988)

  10. 10

    Yao, Z. et al. Elimination of apolipoprotein B48 formation in rat hepatoma cell lines transfected with mutant human apolipoprotein B cDNA constructs. J. Biol. Chem. 267, 1175–1182 (1992)

  11. 11

    Goldberg, I. J. et al. The NH2-terminal region of apolipoprotein B is sufficient for lipoprotein association with glycosaminoglycans. J. Biol. Chem. 273, 35355–35361 (1998)

  12. 12

    Simionescu, M. & Simionescu, N. Endothelial transport of macromolecules: transcytosis and endocytosis. A look from cell biology. Cell Biol. Rev. 25, 5–78 (1991)

  13. 13

    Tangirala, R. K., Rubin, E. M. & Palinski, W. Quantitation of atherosclerosis in murine models: Correlation between lesions in the aortic origin and in the entire aorta, and differences in the extent of lesions between sexes in LDL receptor-deficient and apolipoprotein E-deficient mice. J. Lipid Res. 36, 2320–2328 (1995)

  14. 14

    Puhl, H., Waeg, G. & Esterbauer, H. Methods to determine oxidation of low-density lipoproteins. Methods Enzymol. 233, 425–441 (1994)

  15. 15

    Yagi, K. A simple fluorometric assay for lipoperoxide in blood plasma. Biochem. Med. 15, 212–216 (1976)

  16. 16

    Ji, Z. S., Pitas, R. E. & Mahley, R. W. Differential cellular accumulation/retention of apolipoprotein E mediated by cell surface heparan sulfate proteoglycans. Apolipoproteins E3 and E2 greater than E4. J. Biol. Chem. 273, 13452–13460 (1998)

  17. 17

    Brissette, L., Roach, P. D. & Noel, S. P. The effects of liposome-reconstituted apolipoproteins on the binding of rat intermediate density lipoproteins to rat liver membranes. J. Biol. Chem. 261, 11631–11638 (1986)

  18. 18

    Milne, R. W., Theolis, R. Jr, Verdery, R. B. & Marcel, Y. L. Characterization of monoclonal antibodies against human low density lipoprotein. Arteriosclerosis 3, 23–30 (1983)

  19. 19

    Purcell-Huynh, D. A. et al. Transgenic mice expressing high levels of human apolipoprotein B develop severe atherosclerotic lesions in response to a high-fat diet. J. Clin. Invest. 95, 2246–2257 (1995)

  20. 20

    Nicoletti, A., Kaveri, S., Caligiuri, G., Bariety, J. & Hansson, G. K. Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J. Clin. Invest. 102, 910–918 (1998)

  21. 21

    Mahley, R. W. et al. Inhibition of lipoprotein binding to cell surface receptors of fibroblasts following selective modification of arginyl residues in arginine-rich and B apoproteins. J. Biol. Chem. 252, 7279–7287 (1977)

  22. 22

    Ohlsson, B. G. et al. Oxidized low density lipoprotein inhibits lipopolysaccharide-induced binding of nuclear factor-kappaB to DNA and the subsequent expression of tumour necrosis factor-α and interleukin-1β in macrophages. J. Clin. Invest. 98, 78–89 (1996)

  23. 23

    McFarlane, A. S. Efficient trace-labelling of proteins with iodine. Nature 182, 53 (1958)

  24. 24

    Hurt-Camejo, E. et al. Effect of arterial proteoglycans and glycosaminoglycans on low density lipoprotein oxidation and its uptake by human macrophages and arterial smooth muscle cells. Arterioscler. Thromb. 12, 569–583 (1992)

  25. 25

    Bligh, E. G. & Dyer, W. J. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917 (1959)

  26. 26

    Randle, D. H., Zindy, F., Sherr, C. J. & Roussel, M. F. Differential effects of p19Arf and p16Ink4a loss on senescence of murine bone marrow-derived preB cells and macrophages. Proc. Natl Acad. Sci. USA 98, 9654–9659 (2001)

  27. 27

    Stanley, E. R. The macrophage colony-stimulating factor, CSF-1. Methods Enzymol. 116, 564–587 (1985)

  28. 28

    Schwenke, D. C. Gender differences in intima-media permeability to low-density lipoprotein at atherosclerosis-prone aortic sites in rabbits. Lack of effect of 17 β-estradiol. Arterioscler. Thromb. Vasc. Biol. 17, 2150–2157 (1997)

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Acknowledgements

We thank L. Lindgren, C. Ullström and A. Lidell for technical assistance, O. Nerman and K. Wiklander for statistical analysis, D. Schwenke for advice with retention studies. K. Weisgraber for comments on the manuscript, and S. Ordway and G. Howard for editorial assistance. This work was supported by the Swedish Medical Research Council, The Swedish Foundation for Strategic Research, The Swedish Heart–Lung Foundation, and in part by a National Institutes of Health grant..

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Author notes

  1. Kristina Skålén, Maria Gustafsson and Thomas L. Innerarity: These authors contributed equally to this work

Affiliations

  1. Wallenberg Laboratory for Cardiovascular Research, Göteborg University, Göteborg, S-4345, Sweden

    • Kristina Skålén
    • , Maria Gustafsson
    • , Ellen Knutsen Rydberg
    • , Lillemor Mattsson Hultén
    • , Olov Wiklund
    •  & Jan Borén
  2. Gladstone Institute of Cardiovascular Disease, San Francisco, 94141-9100, California, USA

    • Thomas L. Innerarity

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The authors declare that they have no competing financial interests

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Correspondence to Jan Borén.

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https://doi.org/10.1038/nature00804

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