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Mechanisms of Disease: macrophage-derived foam cells emerging as therapeutic targets in atherosclerosis

Abstract

The limited efficacy of current treatment strategies for targeting atherosclerosis and its complications requires new therapeutic options to be explored. From early fatty-streak lesions to advanced plaques, macrophage-derived foam cells are integral to the development and progression of atherosclerosis. Elucidation of molecular and cellular processes involving macrophages has led to numerous therapeutic targets being suggested. Potential sites of intervention range from monocyte recruitment, through cholesterol uptake and esterification, to cholesterol evacuation and macrophage egress from plaque. In addition, complex patterns of transcriptional regulation of genes involved in macrophage lipid homeostasis and in the regulation of inflammation have been partly unraveled. Recognition of ATP-binding cassette cholesterol transport mechanisms and cellular interactions with cholesterol-accepting apolipoproteins (or synthetic mimetics) opens up new potential therapies to induce atherosclerosis regression in humans. This review presents a systematic evaluation of actual and potential macrophage-directed pharmacologic interventions. It reflects the timely convergence of three important strands: advances in molecular and cell biology that have suggested therapeutic targets in macrophages; the development of multiple classes of drugs targeting these pathways; and the emergence of sensitive imaging techniques that have enabled identification of changes in plaque size and composition in response to treatment.

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Figure 1: Macrophages from the aortic root of an apolipoprotein E knockout mouse.
Figure 2: Summary of potentially intervention-sensitive events in atherogenesis.
Figure 3: Transcriptional regulation mediated by PPARs and LXRs.

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References

  1. Williams KJ and Tabas I (1995) The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 15: 551–561

    Article  CAS  Google Scholar 

  2. Gerszten RE et al. (1999) MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 398: 718–723

    Article  CAS  Google Scholar 

  3. Cybulsky MI and Gimbrone MA Jr (1991) Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251: 788–791

    Article  CAS  Google Scholar 

  4. Li AC and Glass CK (2002) The macrophage foam cell as a target for therapeutic intervention. Nat Med 8: 1235–1242

    Article  CAS  Google Scholar 

  5. Greaves DR and Gordon S (2005) Thematic review series: the immune system and atherogenesis. recent insights into the biology of macrophage scavenger receptors. J Lipid Res 46: 11–20

    Article  CAS  Google Scholar 

  6. Davies MJ et al. (1993) Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 69: 377–381

    Article  CAS  Google Scholar 

  7. Galis ZS et al. (1994) Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 94: 2493–2503

    Article  CAS  Google Scholar 

  8. Wilcox JN et al. (1989) Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A 86: 2839–2843

    Article  CAS  Google Scholar 

  9. Gu L et al. (1998) Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 2: 275–281

    Article  CAS  Google Scholar 

  10. Boring L et al. (1998) Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394: 894–897

    Article  CAS  Google Scholar 

  11. Aiello RJ et al. (1999) Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 19: 1518–1525

    Article  CAS  Google Scholar 

  12. Ni W et al. (2001) New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice. Circulation 103: 2096–2101

    Article  CAS  Google Scholar 

  13. Veillard NR et al. (2004) Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. Circ Res 94: 253–261

    Article  CAS  Google Scholar 

  14. Bursill CA et al. (2004) Broad-spectrum CC-chemokine blockade by gene transfer inhibits macrophage recruitment and atherosclerotic plaque formation in apolipoprotein E-knockout mice. Circulation 110: 2460–2466

    Article  CAS  Google Scholar 

  15. Dansky HM et al. (2001) Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler Thromb Vasc Biol 21: 1662–1667

    Article  CAS  Google Scholar 

  16. Huo Y et al. (2000) Role of vascular cell adhesion molecule-1 and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions. Circ Res 87: 153–159

    Article  CAS  Google Scholar 

  17. Shih DM et al. (2000) Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem 275: 17527–17535

    Article  CAS  Google Scholar 

  18. Quarck R et al. (2001) Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice. Circulation 103: 2495–2500

    Article  CAS  Google Scholar 

  19. Mackness B et al. (2003) Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study. Circulation 107: 2775–2779

    Article  CAS  Google Scholar 

  20. Winkler K et al. (2005) Platelet-activating factor acetylhydrolase activity indicates angiographic coronary artery disease independently of systemic inflammation and other risk factors: the Ludwigshafen Risk and Cardiovascular Health Study. Circulation 111: 980–987

    Article  CAS  Google Scholar 

  21. Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360: 23–33

  22. Pan M et al. (2004) Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. J Clin Invest 113: 1277–1287

    Article  CAS  Google Scholar 

  23. Rodriguez A et al. (1999) Novel effects of the acyl-coenzyme A:Cholesterol acyltransferase inhibitor 58-035 on foam cell development in primary human monocyte-derived macrophages. Arterioscler Thromb Vasc Biol 19: 2199–2206

    Article  CAS  Google Scholar 

  24. Tanaka H et al. (1994) Effect of the acyl-CoA:cholesterol acyltransferase inhibitor, E5324, on experimental atherosclerosis in rabbits. Atherosclerosis 107: 187–201

    Article  CAS  Google Scholar 

  25. Kusunoki J et al. (2001) Acyl-CoA:cholesterol acyltransferase inhibition reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 103: 2604–2609

    Article  CAS  Google Scholar 

  26. Tardif JC et al. (2004) Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 110: 3372–3377

    Article  CAS  Google Scholar 

  27. de Medina P et al. (2004) Tamoxifen is a potent inhibitor of cholesterol esterification and prevents the formation of foam cells. J Pharmacol Exp Ther 308: 1165–1173

    Article  CAS  Google Scholar 

  28. Bodzioch M et al. (1999) The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22: 347–351

    Article  CAS  Google Scholar 

  29. McNeish J et al. (2000) High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Natl Acad Sci U S A 97: 4245–4250

    Article  CAS  Google Scholar 

  30. Haghpassand M et al. (2001) Monocyte/macrophage expression of ABCA1 has minimal contribution to plasma HDL levels. J Clin Invest 108: 1315–1320

    Article  CAS  Google Scholar 

  31. Aiello RJ et al. (2002) Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler Thromb Vasc Biol 22: 630–637

    Article  CAS  Google Scholar 

  32. Joyce CW et al. (2002) The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci U S A 99: 407–412

    Article  CAS  Google Scholar 

  33. Wang N et al. (2004) ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci U S A 101: 9774–9779

    Article  CAS  Google Scholar 

  34. Chinetti G et al. (2001) PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 7: 53–58

    Article  CAS  Google Scholar 

  35. Sparrow CP et al. (2002) A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux. J Biol Chem 277: 10021–10027

    Article  CAS  Google Scholar 

  36. Brewer HB Jr (2004) High-density lipoproteins: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol 24: 387–391

    Article  CAS  Google Scholar 

  37. Nissen SE et al. (2003) Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290: 2292–2300

    Article  CAS  Google Scholar 

  38. Navab M et al. (2004) Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice. Circulation 109: 3215–3220

    Article  CAS  Google Scholar 

  39. Plutzky J (2003) Medicine. PPARs as therapeutic targets: reverse cardiology? Science 302: 406–407

    Article  CAS  Google Scholar 

  40. Wang YX et al. (2003) Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113: 159–170

    Article  CAS  Google Scholar 

  41. Ricote M et al. (2004) Decoding transcriptional programs regulated by PPARs and LXRs in the macrophage: effects on lipid homeostasis, inflammation, and atherosclerosis. Arterioscler Thromb Vasc Biol 24: 230–239

    Article  CAS  Google Scholar 

  42. Nagy L et al. (1998) Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93: 229–240

    Article  CAS  Google Scholar 

  43. Tontonoz P et al. (1998) PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93: 241–252

    Article  CAS  Google Scholar 

  44. Chinetti G et al. (2003) Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages. Circ Res 92: 212–217

    Article  CAS  Google Scholar 

  45. Chinetti G et al. (1998) Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 273: 25573–25580

    Article  CAS  Google Scholar 

  46. Ricote M et al. (1998) Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc Natl Acad Sci U S A 95: 7614–7619

    Article  CAS  Google Scholar 

  47. Li AC et al. (2004) Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ. J Clin Invest 114: 1564–1576

    Article  CAS  Google Scholar 

  48. Yeung AC and Tsao P (2002) Statin therapy: beyond cholesterol lowering and antiinflammatory effects. Circulation 105: 2937–2938

    Article  Google Scholar 

  49. Corti R et al. (2002) Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 106: 2884–2887

    Article  CAS  Google Scholar 

  50. Reis ED et al. (2001) Dramatic remodeling of advanced atherosclerotic plaques of the apolipoprotein E-deficient mouse in a novel transplantation model. J Vasc Surg 34: 541–547

    Article  CAS  Google Scholar 

  51. Llodra J et al. (2004) Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci U S A 101: 11779–11784

    Article  CAS  Google Scholar 

  52. Rudd JH et al. (2002) Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation 105: 2708–2711

    Article  CAS  Google Scholar 

  53. Tearney GJ et al. (2003) Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography. Circulation 107: 113–119

    Article  Google Scholar 

  54. Verheye S et al. (2002) In vivo temperature heterogeneity of atherosclerotic plaques is determined by plaque composition. Circulation 105: 1596–1601

    Article  Google Scholar 

  55. Kooi ME et al. (2003) Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation 107: 2453–2458

    Article  CAS  Google Scholar 

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Correspondence to Robin P Choudhury.

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Glossary

CC CHEMOKINES

Glycoproteins with potent chemoattractant properties, especially to monocytes; 'CC' refers to adjacent cysteine residues

MONOCYTE CHEMOATTRACTANT PROTEIN-1

A chemoattractant involved in recruitment of monocytes to the vessel wall; also known in standardized nomenclature as CCL2

RANTES (REGULATED UPON ACTIVATION, NORMAL T-CELL EXPRESSED, AND PRESUMABLY SECRETED)

A potent mononuclear cell chemoattractant; also known by standardized nomenclature as CCL5

15-DEOXYPROSTAGLANDIN J2

Product of arachidonic acid metabolism and an endogenous ligand of peroxisome proliferator-activated receptor γ

OPTICAL COHERENCE TOMOGRAPHY

Forms images from reflected infrared light; heterogeneity of optical index of refraction leads to optical scattering and a stronger signal

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Choudhury, R., Lee, J. & Greaves, D. Mechanisms of Disease: macrophage-derived foam cells emerging as therapeutic targets in atherosclerosis. Nat Rev Cardiol 2, 309–315 (2005). https://doi.org/10.1038/ncpcardio0195

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  • DOI: https://doi.org/10.1038/ncpcardio0195

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