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Vascular inflammation and activation: new targets for lipid lowering

M. Aikawa* and P. Libby

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, U.S.A.

* Correspondence: Masanori Aikawa, MD, PhD, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC309, Boston, MA 02115, U.S.A.

Abstract

Inflammatory cells, including macrophages, in atheroma overexpress matrix metalloproteinases (MMPs) and tissue factor which contribute to plaque rupture and thrombosis. Activated smooth muscle cells (SMCs) in the plaque's fibrous cap also express MMPs and tissue factor. Lipid lowering appears to reduce the incidence of acute coronary events in patients by stabilizing atherosclerotic plaques. To improve mechanistic understanding, we tested the hypothesis that experimental manipulation of cholesterol level improves features of atheroma related to their propensity to provoke acute thrombotic complications. In rabbits with established atheroma, dietary lipid lowering reduced accumulation of macrophages expressing MMPs and increased collagen, a key determinant of plaque stability. Lipid lowering also decreased expression of tissue factor and its inducer, CD40 ligand. SMCs in the fibrous cap of rabbit atheroma expressed less MMP and tissue factor after lipid lowering. We have recently found that treatment with an HMG-CoA reductase inhibitor, cerivastatin, retards macrophage accumulation in atheroma of Watanabe heritable hyperlipidaemic (WHHL) rabbits, probably in part by suppressing proliferation. Macrophage expression of MMPs and tissue factor also decreased with cerivastatin treatment in vivo and in vitro. These results support the view that lipid lowering reduces acute thrombotic complications of atherosclerosis in patients by attenuating vascular inflammation.

Key Words: Lipid lowering • atheroma • atherosclerosis

Footnotes

The studies from the Cardiovascular Division of the Brigham and Women's Hospital referred to here were supported by grants from the National Heart, Lung, and Blood Institute (HL-34636, PO1 HL48743) and unrestricted research and educational gifts from Bayer Pharmaceuticals. We acknowledge all our colleagues and collaborators including Elena Rabkin, Seigo Sugiyama, Sami J. Voglic, Masashi Shiomi, Yoshikatsu Okada, Frederick J. Schoen, Mark B. Taubman, John T. Fallon, Eugenia Shvartz, Christopher C. Hill, Yoshihiro Fukumoto, Joseph L. Witztum, Ryozo Nagai, Elissa Simon-Morrissey and Dmitriy Zvagelsky who contributed to the experiments described. We also thank Karen E. Williams for her editorial expertise.

References

  1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242–250Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:310–318[Web of Science][Medline]
  2. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–2850[Free Full Text]
  3. Berliner JA, Navab M, Fogelman AM, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995;91:2488–2496[Abstract/Free Full Text]
  4. 4S Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389[CrossRef][Web of Science][Medline]
  5. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–1307[Abstract/Free Full Text]
  6. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med. 1996;335:1001–1009[Abstract/Free Full Text]
  7. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. J Am Med Assoc. 1998;279:1615–1622[Abstract/Free Full Text]
  8. Ambrose JA, Winters SL, Stern A, et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol. 1985;5:609–616[Abstract]
  9. Ambrose JA, Tannenbaum MA, Alexopoulos D, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol. 1988;12:56–62[Abstract]
  10. Little WC. Angiographic assessment of the culprit coronary artery lesion before acute myocardial infarction. Am J Cardiol. 1990;66:44G–47G[CrossRef][Medline]
  11. Davies MJ. Stability and instability: two faces of coronary atherosclerosis. The Paul Dudley White Lecture 1995. Circulation. 1996;94:2013–2020[Free Full Text]
  12. Lee RT, Libby P. The unstable atheroma. Arterioscler Thromb Vasc Biol. 1997;17:1859–1867[Free Full Text]
  13. Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of fibrous cap thickness on peak circumferential stress in model atherosclerotic vessels. Circ Res. 1992;71:850–858[Abstract/Free Full Text]
  14. Rekhter MD, Hicks GW, Brammer DW. Hypercholesterolemia causes mechanical weakening of rabbit atheroma: local collagen loss as a prerequisite of plaque rupture. Circ Res. 2000;86:101–108[Abstract/Free Full Text]
  15. Davies MJ, Thomas AC. Plaque fissuring—the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J. 1985;53:363–373[Free Full Text]
  16. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89:36–44[Abstract/Free Full Text]
  17. Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation. 1996;93:1354–1363[Abstract/Free Full Text]
  18. Libby P, Geng YJ, Aikawa M, et al. Macrophages and atherosclerotic plaque stability. Curr Opin Lipidol. 1996;7:330–335[Web of Science][Medline]
  19. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation. 1994;90:775–778[Abstract/Free Full Text]
  20. Dollery CM, McEwan JR, Henney AM. Matrix metalloproteinases and cardiovascular disease. Circ Res. 1995;77:863–868[Free Full Text]
  21. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:2493–2503
  22. Galis ZS, Sukhova GK, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci USA. 1995. p. 402–406
  23. Nikkari ST, O'Brien KD, Ferguson M, et al. Interstitial collagenase (MMP-1) expression in human carotid atherosclerosis. Circulation. 1995;92:1393–1398[Abstract/Free Full Text]
  24. Aikawa M, Rabkin E, Okada Y, et al. Lipid lowering by diet reduces matrix metalloproteinase activity and increases collagen content of rabbit atheroma: a potential mechanism of lesion stabilization. Circulation. 1998;97:2433–2444[Abstract/Free Full Text]
  25. Sukhova G, Schönbeck U, Rabkin E, et al. Evidence of increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation. 1999;99:2503–2509[Abstract/Free Full Text]
  26. Shah PK, Falk E, Badimon JJ, et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation. 1995;92:1565–1569
  27. Henney AM, Wakeley PR, Davies MJ, et al. Localization of stromelysin gene expression in atherosclerotic plaques by in situ hybridization. Proc Natl Acad Sci USA. 1991. p. 8154–8158
  28. Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM. Identification of 92-kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation. 1995;91:2125–2131[Abstract/Free Full Text]
  29. Sukhova GK, Shi GP, Simon DI, Chapman HA, Libby P. Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J Clin Invest. 1998;102:576–583[Web of Science][Medline]
  30. Amento EP, 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. 1991;11:1223–1230[Abstract/Free Full Text]
  31. Rekhter MD, Zhang K, Narayanan AS, Phan S, Schork MA, Gordon D. Type I collagen gene expression in human atherosclerosis. Localization to specific plaque regions. Am J Pathol. 1993;143:1634–1648[Abstract]
  32. Taubman MB, Fallon JT, Schecter AD, et al. Tissue factor in the pathogenesis of atherosclerosis. Thromb Haemost. 1997;78:200–204[Web of Science][Medline]
  33. Libby P, Mach F, Schönbeck U, Bourcier T, Aikawa M. Regulation of the thrombotic potential of atheroma. Thromb Haemost. 1999;82:736–741[Web of Science][Medline]
  34. Toschi V, Gallo R, Lettino M, et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997;95:594–599[Abstract/Free Full Text]
  35. Wilcox JN, Smith KM, Schwartz SM, Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA. 1989. p. 2839–2843
  36. Thiruvikraman SV, Guha A, Roboz J, Taubman MB, Nemerson Y, Fallon JT. In situ localization of tissue factor in human atherosclerotic plaques by binding of digoxigenin-labeled factors VIIa and X. Lab Invest. 1996;75:451–461[Web of Science][Medline]
  37. Moreno PR, Bernardi VH, Lopez-Cuellar J, et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996;94:3090–3097[Abstract/Free Full Text]
  38. Ardissino D, Merlini PA, Ariens R, Coppola R, Bramucci E, Mannucci PM. Tissue-factor antigen and activity in human coronary atherosclerotic plaques. Lancet. 1997;349:769–771[CrossRef][Web of Science][Medline]
  39. Kaikita K, Ogawa H, Yasue H, et al. Tissue factor expression on macrophages in coronary plaques in patients with unstable angina. Arterioscler Thromb Vasc Biol. 1997;17:2232–2237[Abstract/Free Full Text]
  40. Mach F, Schönbeck U, Sukhova GK, et al. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci USA. 1997. p. 1931–1936
  41. Mach F, Schönbeck U, Bonnefoy JY, Pober JS, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation. 1997;96:396–399[Abstract/Free Full Text]
  42. Schwartz SM, deBlois D, O'Brien ER. The intima. Soil for atherosclerosis and restenosis. Circ Res. 1995;77:445–465[Free Full Text]
  43. Aikawa M, Sivam PN, Kuro-o M, et al. Human smooth muscle myosin heavy chain isoforms as molecular markers for vascular development and atherosclerosis. Circ Res. 1993;73:1000–1012[Abstract/Free Full Text]
  44. Owens GK. Regulation of differentiation of vascular smooth muscle cells. Physiol Rev. 1995;75:487–517[Abstract/Free Full Text]
  45. Aikawa M, Voglic SJ, Sugiyama S, et al. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation. 1999;100:1215–1222[Abstract/Free Full Text]
  46. Cotran RS, Briscoe DM. Endothelial cells in inflammation. Kelly W, Harris E, Ruddy S, Sledge C. Textbook of leumatology. Philadelphia: WB Saunders; 1997. p. 183–198
  47. Li H, Cybulsky MI, Gimbrone MA Jr, Libby P. An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb. 1993;13:197–204[Abstract/Free Full Text]
  48. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature (London). 1998;394:894–897[CrossRef][Medline]
  49. Gu L, Okada Y, Clinton SK, et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998;2:275–281[CrossRef][Web of Science][Medline]
  50. Kunsch C, Medford RM. Oxidative stress as a regulator of gene expression in the vasculature. Circ Res. 1999;85:753–766[Abstract/Free Full Text]
  51. Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet. 1994;344:793–795[CrossRef][Web of Science][Medline]
  52. Haberland ME, Fong D, Cheng L. Malondialdehydealtered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits. Science. 1988;241:215–218[Abstract/Free Full Text]
  53. Yla-Herttuala S, Palinski W, Rosenfeld ME, et al. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989;84:1086–1095
  54. Kume N, Cybulsky MI, Gimbrone MA Jr. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest. 1992;90:1138–1144
  55. Khan BV, Parthasarathy SS, Alexander RW, Medford RM. Modified low density lipoprotein 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
  56. Cushing SD, Berliner JA, Valente AJ, et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA. 1990. p. 5134–5138
  57. Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression. New insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781–1791[Abstract/Free Full Text]
  58. Blankenhorn DH, Hodis HN. George Lyman Duff Memorial Lecture. Arterial imaging and atherosclerosis reversal. Arterioscler Thromb. 1994;14:177–192[Abstract/Free Full Text]
  59. Libby P, Aikawa M. New insights into plaque stabilisation by lipid lowering. Drugs. 1998;56:9–13
  60. Aikawa M, Rabkin E, Voglic SJ, et al. Lipid lowering promotes accumulation of mature smooth muscle cells expressing smooth muscle myosin heavy chain isoforms in rabbit atheroma. Circ Res. 1998;83:1015–1026[Abstract/Free Full Text]
  61. Aikawa M, Sugiyama S, Rabkin E, et al. Dietary lipid lowering reduces oxidative stress and endothelial cell activation: potential mechanisms of atherosclerotic plaque stabilization (Abstr). Circulation. 1999;100:I–542
  62. Aikawa M, Rabkin E, Sugiyama S. Cerivastatin, an HMG-CoA reductase inhibitor, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro. Circulation. 2001;103:276–283[Abstract/Free Full Text]
  63. McConnell MV, Aikawa M, Myer SS, Ganz P, Libby P, Lee RT. Magnetic resonance imaging of rabbit aortic atherosclerosis in response to dietary lipid lowering. Arterioscler Thromb Vasc Biol. 1999;19:1956–1959[Abstract/Free Full Text]
  64. Kockx MM, De Meyer GR, Buyssens N, Knaapen MW, Bult H, Herman AG. Cell composition, replication, and apoptosis in atherosclerotic plaques after 6 months of cholesterol withdrawal. Circ Res. 1998;83:378–387[Abstract/Free Full Text]
  65. Holycross BJ, Blank RS, Thompson MM, Peach MJ, Owens GK. Platelet-derived growth factor-BB-induced suppression of smooth muscle cell differentiation. Circ Res. 1992;71:1525–1532[Abstract/Free Full Text]
  66. Corsini A, Bellosta S, Baetta R, Fumagalli R, Paoletti R, Bernini F. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther. 1999;84:413–428[CrossRef][Web of Science][Medline]
  67. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999;100:230–235[Abstract/Free Full Text]
  68. Shiomi M, Ito T, Tsukada T, et al. Reduction of serum cholesterol levels alters lesional composition of atherosclerotic plaques. Effect of pravastatin sodium on atherosclerosis in mature WHHL rabbits. Arterioscler Thromb Vasc Biol. 1995;15:1938–1944[Abstract/Free Full Text]
  69. Shiomi M, Ito T. Effect of cerivastatin sodium, a new inhibitor of HMG-CoA reductase, on plasma lipid levels, progression of atherosclerosis, and the lesional composition in the plaques of WHHL rabbits. Br J Pharmacol. 1999;126:961–968[CrossRef][Web of Science][Medline]
  70. Shiomi M, Ito T, Watanabe Y, et al. Suppression of established atherosclerosis and xanthomas in mature WHHL rabbits by keeping their serum cholesterol levels extremely low. Effect of pravastatin sodium in combination with cholestyramine. Atherosclerosis. 1990;83:69–80[CrossRef][Web of Science][Medline]
  71. Gordon D, Reidy MA, Benditt EP, Schwartz SM. Cell proliferation in human coronary arteries. Proc Natl Acad Sci USA. 1990. p. 4600–4604
  72. Rosenfeld ME, Ross R. Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits. Arteriosclerosis. 1990;10:680–687[Abstract/Free Full Text]
  73. Rekhter MD, Gordon D. Active proliferation of different cell types, including lymphocytes, in human atherosclerotic plaques. Am J Pathol. 1995;147:668–677[Abstract]
  74. Alison M, Chaudry Z, Baker J, Lauder I, Pringle H. Liver regeneration: a comparison of in situ hybridization for histone mRNA with bromodeoxyuridine labeling for the detection of S-phase cells. J Histochem Cytochem. 1994;42:1603–1608[Abstract]
  75. Sakai M, Miyazaki A, Hakamata H, et al. Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages. J Biol Chem. 1994;269:31430–31435[Abstract/Free Full Text]
  76. Hamilton JA, Myers D, Jessup W, et al. Oxidized LDL can induce macrophage survival, DNA synthesis, and enhanced proliferative response to CSF-1 and GM-CSF. Arterioscler Thromb Vasc Biol. 1999;19:98–105[Abstract/Free Full Text]
  77. Sakai M, Kobori S, Matsumura T, et al. HMG-CoA reductase inhibitors suppress macrophage growth induced by oxidized low density lipoprotein. Atherosclerosis. 1997;133:51–59[CrossRef][Web of Science][Medline]
  78. Stein E, Isaacsohn J, Stoltz R, et al. Pharmacodynamics, safety, tolerability, and pharmacokinetics of the 0·8-mg dose of cerivastatin in patients with primary hypercholesterolemia. Am J Cardiol. 1999;83:1433–1436[CrossRef][Web of Science][Medline]
  79. Schönbeck U, Mach F, Sukhova GK, et al. Regulation of matrix metalloproteinase expression in human vascular smooth muscle cells by T lymphocytes: a role for CD40 signaling in plaque rupture? Circ Res. 1997;81:448–454[Abstract/Free Full Text]
  80. Bellosta S, Via D, Canavesi M, et al. HMG-CoA reductase inhibitors reduce MMP-9 secretion by macrophages. Arterioscler Thromb Vasc Biol. 1998;18:1671–1678[Abstract/Free Full Text]
  81. Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages. A novel mechanism of protection against athero-thrombosis. Arterioscler Thromb Vasc Biol. 1997;17:265–272[Abstract/Free Full Text]
  82. Corsini A, Arnaboldi L, Raiteri M, et al. Effect of the new HMG-CoA reductaase inhibitor cerivastatin (BAY W6228) on migration, proliferation and cholesterol synthesis in arterial myocytes. Pharmacol Res. 1996;33:55–61[CrossRef][Web of Science][Medline]
  83. Igarashi M, Takeda Y, Mori S, et al. Suppression of neo-intimal thickening by a newly developed HMG-CoA reductase inhibitor, BAYW6228, and its inhibitory effect on vascular smooth muscle cell growth. Br J Pharmacol. 1997;120:1172–1178[CrossRef][Web of Science][Medline]
  84. Corsini A, Pazzucconi F, Pfister P, Paoletti R, Sirtori CR. Inhibitor of proliferation of arterial smooth-muscle cells by fluvastatin (letter). Lancet. 1996;348:1584[Web of Science][Medline]
  85. Laufs U, Marra D, Node K, Liao JK. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J Biol Chem. 1999;274:21926–21931[Abstract/Free Full Text]
  86. Guijarro C, Blanco-Colio LM, Ortego M, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res. 1998;83:490–500[Abstract/Free Full Text]
  87. Geng YJ, Libby P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme. Am J Pathol. 1995;147:251–266[Abstract]

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M. Aikawa, S. Sugiyama, C. C. Hill, S. J. Voglic, E. Rabkin, Y. Fukumoto, F. J. Schoen, J. L. Witztum, and P. Libby
Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma
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