[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Stabilization of atherosclerotic plaques: New mechanisms and clinical targets

Nature Medicine volume 8, pages 1257–1262 (2002)Cite this article

An Erratum to this article was published on 01 January 2003

Research points to pivotal roles for lipids in the development of atherosclerotic plaques. Lipid-lowering statins substantially reduce acute coronary events resulting from plaque development, but only modestly reduce arterial stenosis. This apparent paradox has shifted the goal of therapy towards plaque stabilization rather than enlargement of the lumen. More thorough understanding of the biology of atherosclerosis should enable us to manipulate plaque stability, and reduce further the acute complications of atherosclerosis.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Large atheroma may not produce flow limiting stenosis.
Figure 2: Evolution and stabilization of 'vulnerable' atherosclerotic plaques.

D. Maizels

Figure 3: Rupture of an inflamed atheroma with thrombus formation.
Figure 4: Stabilization of a disrupted plaque.

References

  1. Falk, E., Shah, P. & Fuster, V. Coronary plaque disruption. Circulation 92, 657–671 (1995).

    Article  CAS  Google Scholar 

  2. Smith, S., Jr. Risk-reduction therapy: The challenge to change. Circulation 93, 2205–2211 (1996).

    Article  Google Scholar 

  3. Roberts, W.C. Relationship between coronary thrombosis and myocardial infarction. Mod. Concepts Cardiovasc. Dis. 41, 7–10 (1972).

    CAS  PubMed  Google Scholar 

  4. Hackett, D., Davies, G. & Maseri, A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur. Heart J. 9, 1317–1323 (1988).

    Article  CAS  Google Scholar 

  5. Farb, A. et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation 93, 1354–1363 (1996).

    Article  CAS  Google Scholar 

  6. Davies, M.J. Stability and instability: The two faces of coronary atherosclerosis. The Paul Dudley White Lecture, 1995. Circulation 94, 2013–2020 (1996).

    Article  CAS  Google Scholar 

  7. Libby, P. The molecular bases of the acute coronary syndromes. Circulation 91, 2844–2850 (1995).

    Article  CAS  Google Scholar 

  8. Amento, E.P., Ehsani, N., Palmer, H. & Libby, P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 11, 1223–1230 (1991).

    Article  CAS  Google Scholar 

  9. Gupta, S. et al. IFN-γ potentiates atherosclerosis in ApoE knock-out mice. J. Clin. Invest. 99, 2752–2761 (1997).

    Article  CAS  Google Scholar 

  10. Nakata, Y. & Maeda, N. Vulnerable atherosclerotic plaque morphology in apolipoprotein E-deficient mice unable to make ascorbic acid. Circulation 105, 1485–1490 (2002).

    Article  CAS  Google Scholar 

  11. Galis, Z., Sukhova, G., Lark, M. & Libby, P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J. Clin. Invest. 94, 2493–2503 (1994).

    Article  CAS  Google Scholar 

  12. Nikkari, S.T. et al. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation 92, 1393–1398 (1995).

    Article  CAS  Google Scholar 

  13. Sukhova, G.K. et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 99, 2503–2509 (1999).

    Article  CAS  Google Scholar 

  14. Herman, M.P. et al. Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: A novel collagenolytic pathway suggested by transcriptional profiling. Circulation 104, 1899–1904 (2001).

    Article  CAS  Google Scholar 

  15. Henney, A.M. et al. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc. Natl. Acad. Sci. USA 88, 8154–8158 (1991).

    Article  CAS  Google Scholar 

  16. Yanagi, H., Sasaguri, Y., Sugama, K., Morimatsu, M. & Nagase, H. Production of tissue collagenase (matrix metalloproteinase 1) by human aortic smooth muscle cells in response to platelet-derived growth factor. Atherosclerosis 91, 207–216 (1991).

    Article  CAS  Google Scholar 

  17. Galis, Z. et al. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ. Res. 75, 181–189 (1994).

    Article  CAS  Google Scholar 

  18. Saren, P., Welgus, H.G. & Kovanen, P.T. TNF-α and IL-1β selectively induce expression of 92-kDa gelatinase by human macrophages. J. Immunol. 157, 4159–4165 (1996).

    CAS  Google Scholar 

  19. Rajagopalan, S., Meng, X.P., Ramasamy, S., Harrison, D.G. & Galis, Z.S. Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J. Clin. Invest. 98, 2572–2579 (1996).

    Article  CAS  Google Scholar 

  20. Davies, M.J., Richardson, P.D., Woolf, N., Katz, D.R. & Mann, J. Risk of thrombosis in human atherosclerotic plaques: Role of extracellular lipid, macrophage, and smooth muscle cell content. Br. Heart J. 69, 377–381 (1993).

    Article  CAS  Google Scholar 

  21. van der Wal, A.C., Becker, A.E., van der Loos, C.M. & Das, P.K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89, 36–44 (1994).

    Article  CAS  Google Scholar 

  22. Geng, Y.-J. & Libby, P. Evidence for apoptosis in advanced human atheroma. Co-localization with interleukin-1β-converting enzyme. Am. J. Pathol. 147, 251–266 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wilcox, J.N., Smith, K.M., Schwartz, S.M. & Gordon, D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc. Natl. Acad. Sci. USA 86, 2839–2843 (1989).

    Article  CAS  Google Scholar 

  24. Drake, T.A., Morrissey, J.H. & Edgington, T.S. Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am. J. Pathol. 134, 1087–1097 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mach, F., Schoenbeck, U., Bonnefoy, J.-Y., Pober, J. & Libby, P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40. Induction of collagenase, stromelysin, and tissue factor. Circulation 96, 396–399 (1997).

    Article  CAS  Google Scholar 

  26. Brown, B.G., Zhao, X.Q., Sacco, D.E. & Albers, J.J. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 87, 1781–1791 (1993).

    Article  CAS  Google Scholar 

  27. Blankenhorn, D.H. & Hodis, H.N. Arterial imaging and atherosclerosis reversal. Arterioscler. Thromb. 14, 177–192 (1994).

    Article  CAS  Google Scholar 

  28. Aikawa, M. et al. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: A potential mechanism of lesion stabilization. Circulation 97, 2433–2444 (1998).

    Article  CAS  Google Scholar 

  29. Aikawa, M. et al. Lipid lowering reduces oxidative stress and endothelial cell activation in rabbit atheroma. Circulation 106, 1390–1396 (2002).

    Article  CAS  Google Scholar 

  30. Kockx, M.M. et al. Cell composition, replication, and apoptosis in atherosclerotic plaques after 6 months of cholesterol withdrawal. Circ. Res. 83, 378–387 (1998).

    Article  CAS  Google Scholar 

  31. Crisby, M. et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: Implications for plaque stabilization. Circulation 103, 926–933 (2001).

    Article  CAS  Google Scholar 

  32. Aikawa, M. et al. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation 100, 1215–1222 (1999).

    Article  CAS  Google Scholar 

  33. Bustos, C. et al. HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis. J. Am. Coll. Cardiol. 32, 2057–2064 (1998).

    Article  CAS  Google Scholar 

  34. Aikawa, M. et al. An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation 103, 276–283 (2001).

    Article  CAS  Google Scholar 

  35. Bocan, T.M. et al. The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits. Arterioscler. Thromb. Vasc. Biol. 20, 70–79 (2000).

    Article  CAS  Google Scholar 

  36. Comparato, C. et al. Clinically relevant pleiotropic effects of statins: Drug properties or effects of profound cholesterol reduction? Nutr. Metab. Cardiovasc. Dis. 11, 328–343 (2001).

    CAS  PubMed  Google Scholar 

  37. Gotto, A.M., Jr. & Farmer, J.A. Pleiotropic effects of statins: Do they matter? Curr. Opin. Lipidol. 12, 391–394 (2001).

    Article  CAS  Google Scholar 

  38. Endres, M. et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc. Natl. Acad. Sci. USA 95, 8880–8885 (1998).

    Article  CAS  Google Scholar 

  39. Diomede, L. et al. In vivo anti-inflammatory effect of statins is mediated by nonsterol mevalonate products. Arterioscler. Thromb. Vasc. Biol. 21, 1327–1332 (2001).

    Article  CAS  Google Scholar 

  40. Sparrow, C.P. et al. Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering. Arterioscler. Thromb. Vasc. Biol. 21, 115–121 (2001).

    Article  CAS  Google Scholar 

  41. Egashira, K. et al. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 89, 2519–2524 (1994).

    Article  CAS  Google Scholar 

  42. Treasure, C. et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N. Engl. J. Med. 332, 481–487 (1995).

    Article  CAS  Google Scholar 

  43. Wilson, S.H. et al. Simvastatin preserves coronary endothelial function in hypercholesterolemia in the absence of lipid lowering. Arterioscler. Thromb. Vasc. Biol. 21, 122–128 (2001).

    Article  CAS  Google Scholar 

  44. Laufs, U., La Fata, V., Plutzky, J. & Liao, J.K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 97, 1129–1135 (1998).

    Article  CAS  Google Scholar 

  45. Hernandez-Perera, O. et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J. Clin. Invest. 101, 2711–2719 (1998).

    Article  CAS  Google Scholar 

  46. Bourcier, T. & Libby, P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells. Arterioscler. Thromb. Vasc. Biol. 20, 556–562 (2000).

    Article  CAS  Google Scholar 

  47. Lopez, S., Peiretti, F., Bonardo, B., Juhan-Vague, I. & Nalbone, G. Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells. Atherosclerosis 152, 359–366 (2000).

    Article  CAS  Google Scholar 

  48. Dangas, G. et al. Pravastatin: An antithrombotic effect independent of the cholesterol-lowering effect. Thromb. Haemost. 83, 688–692 (2000).

    Article  CAS  Google Scholar 

  49. Kureishi, Y. et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nature Med. 6, 1004–1010 (2000).

    Article  CAS  Google Scholar 

  50. Weis, M., Heeschen, C., Glassford, A.J. & Cooke, J.P. Statins have biphasic effects on angiogenesis. Circulation 105, 739–745 (2002).

    Article  CAS  Google Scholar 

  51. Urbich, C., Dernbach, E., Zeiher, A.M. & Dimmeler, S. Double-edged role of statins in angiogenesis signaling. Circ. Res. 90, 737–744 (2002).

    Article  CAS  Google Scholar 

  52. Walter, D.H. et al. Statin therapy accelerates reendothelialization: A novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells. Circulation 105, 3017–3024 (2002).

    Article  CAS  Google Scholar 

  53. Wilson, S.H. et al. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia independent of lipid lowering. Circulation 105, 415–418 (2002).

    Article  CAS  Google Scholar 

  54. Aikawa, M. et al. Human smooth muscle myosin heavy chain isoforms as molecular markers for vascular development and atherosclerosis. Circ. Res. 73, 1000–1012 (1993).

    Article  CAS  Google Scholar 

  55. Brogi, E. et al. Distinct patterns of expression of fibroblast growth factors and their receptors in human atheroma and non-atherosclerotic arteries: Association of acidic FGF with plaque microvessels and macrophages. J. Clin. Invest. 92, 2408–2418 (1993).

    Article  CAS  Google Scholar 

  56. Carmeliet, P. & Jain, R.K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  Google Scholar 

  57. Moulton, K.S. et al. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 99, 1726–1732 (1999).

    Article  CAS  Google Scholar 

  58. Celletti, F.L. et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nature Med. 7, 425–429 (2001).

    Article  CAS  Google Scholar 

  59. Hernandez-Presa, M. et al. Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-κB activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation 95, 1532–1541 (1997).

    Article  CAS  Google Scholar 

  60. Rocha, R. et al. Aldosterone: A mediator of myocardial necrosis and renal arteriopathy. Endocrinology 141, 3871–3878 (2000).

    Article  CAS  Google Scholar 

  61. Marx, N., Sukhova, G.K., Collins, T., Libby, P. & Plutzky, J. PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 99, 3125–3131 (1999).

    Article  CAS  Google Scholar 

  62. Marx, N. et al. PPARα activators inhibit tissue factor expression and activity in human monocytes. Circulation 103, 213–219 (2001).

    Article  CAS  Google Scholar 

  63. Neve, B.P. et al. PPARα agonists inhibit tissue factor expression in human monocytes and macrophages. Circulation 103, 207–212 (2001).

    Article  CAS  Google Scholar 

  64. Marx, N. et al. PPAR activators as antiinflammatory mediators in human T lymphocytes: Implications for atherosclerosis and transplantation-associated arteriosclerosis. Circ. Res. 90, 703–710 (2002).

    Article  CAS  Google Scholar 

  65. Li, A.C. et al. Peroxisome proliferator-activated receptor γ ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J. Clin. Invest. 106, 523–531 (2000).

    Article  CAS  Google Scholar 

  66. Collins, A.R. et al. Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 21, 365–371 (2001).

    Article  CAS  Google Scholar 

  67. Chen, Z. et al. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: Pleiotropic effects on CD36 expression and HDL. Arterioscler. Thromb. Vasc. Biol. 21, 372–377 (2001).

    Article  CAS  Google Scholar 

  68. FitzGerald, G.A. & Patrono, C. The coxibs, selective inhibitors of cyclooxygenase-2. N. Engl. J. Med. 345, 433–442 (2001).

    Article  CAS  Google Scholar 

  69. Schonbeck, U., Sukhova, G.K., Shimizu, K., Mach, F. & Libby, P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc. Natl. Acad. Sci. USA 97, 7458–7463 (2000).

    Article  CAS  Google Scholar 

  70. Lutgens, E. et al. Requirement for CD154 in the progression of atherosclerosis. Nature Med. 5, 1313–1316 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K.E. Williams and D. Lynn for their editorial assistance. The work from our laboratory described herein was supported by grants to P.L. from the Leducq Foundation and the United States National Institutes of Health, National Heart, Lung, and Blood Institute.

Author information

Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Leducq Center for Cardiovascular Research, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Peter Libby & Masanori Aikawa

Authors
  1. Peter Libby
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masanori Aikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Libby.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Libby, P., Aikawa, M. Stabilization of atherosclerotic plaques: New mechanisms and clinical targets. Nat Med 8, 1257–1262 (2002). https://doi.org/10.1038/nm1102-1257

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1102-1257

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing