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.

  • Article
  • Published:

Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development

Nature Medicine volume 14, pages 1059–1066 (2008)Cite this article

Abstract

Increased lipoprotein-associated phospholipase A2 (Lp-PLA2) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA2 is a causative agent. Here we show that selective inhibition of Lp-PLA2 with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA2 activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA2 inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Plasma glucose, cholesterol and Lp-PLA2 activity increase upon DM-HC induction, but only Lp-PLA2 activity is influenced by darapladib.
Figure 2: Influence of DM-HC induction and darapladib on arterial phospholipid composition.
Figure 3: Inhibition of Lp-PLA2 reduces leukocyte subset marker abundance in coronary arteries in the absence of an effect in blood PBMCs.
Figure 4: Darapladib treatment reduces complex coronary lesion development.
Figure 5: Inhibition of Lp-PLA2 results in fewer lesion macrophages in coronary arteries.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Ross, R. Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999).

    Article  PubMed  CAS  Google Scholar 

  2. Hansson, G.K. & Libby, P. The immune response in atherosclerosis: a double-edged sword. Nat. Rev. Immunol. 6, 508–519 (2006).

    Article  PubMed  CAS  Google Scholar 

  3. Steinberg, D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of the statins and the end of the controversy. J. Lipid Res. 47, 1339–1351 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Witztum, J.L. The oxidation hypothesis of atherosclerosis. Lancet 344, 793–795 (1994).

    Article  PubMed  CAS  Google Scholar 

  5. Shah, P.K. Molecular mechanisms of plaque instability. Curr. Opin. Lipidol. 18, 492–499 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Kolodgie, F.D. et al. Intraplaque hemorrhage and progression of coronary atheroma. N. Engl. J. Med. 349, 2316–2325 (2003).

    Article  PubMed  CAS  Google Scholar 

  7. Virmani, R. et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler. Thromb. Vasc. Biol. 20, 1262–1275 (2000).

    Article  PubMed  CAS  Google Scholar 

  8. Spagnoli, L.G. et al. Extracranial thrombotically active carotid plaque as a risk factor for ischemic stroke. J. Am. Med. Assoc. 292, 1845–1852 (2004).

    Article  CAS  Google Scholar 

  9. McIntyre, T.M. et al. Biologically active oxidized phospholipids. J. Biol. Chem. 274, 25189–25192 (1999).

    Article  PubMed  CAS  Google Scholar 

  10. Prescott, S.M. et al. Platelet-activating factor and related lipid mediators. Annu. Rev. Biochem. 69, 419–445 (2000).

    Article  PubMed  CAS  Google Scholar 

  11. Macphee, C.H., Nelson, J.J. & Zalewski, A. Lipoprotein-associated phospholipase A2 as a target of therapy. Curr. Opin. Lipidol. 16, 442–446 (2005).

    Article  PubMed  CAS  Google Scholar 

  12. Zalewski, A. & Macphee, C. Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler. Thromb. Vasc. Biol. 25, 923–931 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Tsimikas, S., Tsironis, L.D. & Tselepis, A.D. New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 27, 2094–2099 (2007).

    Article  PubMed  CAS  Google Scholar 

  14. Garza, C.A. et al. Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin. Proc. 82, 159–165 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Macphee, C.H. et al. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochem. J. 338, 479–487 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Davis, B. et al. Electrospray ionization mass spectrometry identifies substrates and products of lipoprotein-associated phospholipase A2 in oxidized human low density lipoprotein. J. Biol. Chem. 283, 6428–6437 (2008).

    Article  PubMed  CAS  Google Scholar 

  17. Kougias, P. et al. Lysophosphatidylcholine and secretory phospholipase A2 in vascular disease: mediators of endothelial dysfunction and atherosclerosis. Med. Sci. Monit. 12, RA5–RA16 (2006).

    PubMed  CAS  Google Scholar 

  18. Shi, Y. et al. Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses. Atherosclerosis 191, 54–62 (2007).

    Article  PubMed  CAS  Google Scholar 

  19. Carpenter, K.L. et al. Mildly oxidised LDL induces more macrophage death than moderately oxidised LDL: roles of peroxidation, lipoprotein-associated phospholipase A2 and PPARγ. FEBS Lett. 553, 145–150 (2003).

    Article  PubMed  CAS  Google Scholar 

  20. Perez, R. et al. Involvement of group VIA calcium-independent phospholipase A2 in macrophage engulfment of hydrogen peroxide–treated U937 cells. J. Immunol. 176, 2555–2561 (2006).

    Article  PubMed  CAS  Google Scholar 

  21. Aprahamian, T. et al. Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J. Exp. Med. 199, 1121–1131 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kolodgie, F.D. et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 26, 2523–2529 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Blackie, J.A. et al. The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2 . Bioorg. Med. Chem. Lett. 13, 1067–1070 (2003).

    Article  PubMed  CAS  Google Scholar 

  24. Gerrity, R.G. et al. Diabetes-induced accelerated atherosclerosis in swine. Diabetes 50, 1654–1665 (2001).

    Article  PubMed  CAS  Google Scholar 

  25. Mohler, E.R., III et al. Site-specific atherogenic gene expression correlates with subsequent variable lesion development in coronary and peripheral vasculature. Arterioscler. Thromb. Vasc. Biol. 28, 850–855 (2008).

    Article  PubMed  CAS  Google Scholar 

  26. Chatzizisis, Y.S. et al. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular and vascular behavior. J. Am. Coll. Cardiol. 49, 2379–2393 (2007).

    Article  PubMed  CAS  Google Scholar 

  27. Jo, H. et al. Role of NADPH oxidases in disturbed flow- and BMP4- induced inflammation and atherosclerosis. Antioxid. Redox Signal. 8, 1609–1619 (2006).

    Article  PubMed  CAS  Google Scholar 

  28. Schaloske, R.H. & Dennis, E.A. The phospholipase A2 superfamily and its group numbering system. Biochim. Biophys. Acta 1761, 1246–1259 (2006).

    Article  PubMed  CAS  Google Scholar 

  29. Gardner, A.A., Reichert, E.C., Topham, M.K. & Stafforini, D.M. Identification of a domain that mediates association of platelet-activating factor acetylhydrolase with high-density lipoprotein. J. Biol. Chem. 283, 17099–17106 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Stafforini, D.M. et al. Molecular basis of the interaction between plasma platelet-activating factor acetylhydrolase and low density lipoprotein. J. Biol. Chem. 274, 7018–7024 (1999).

    Article  PubMed  CAS  Google Scholar 

  31. Heller, E.A. et al. Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells. Circulation 113, 2301–2312 (2006).

    Article  PubMed  CAS  Google Scholar 

  32. Swirski, F.K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Papaspyridonos, M. et al. Novel candidate genes in unstable areas of human atherosclerotic plaques. Arterioscler. Thromb. Vasc. Biol. 26, 1837–1844 (2006).

    Article  PubMed  CAS  Google Scholar 

  34. Reddy, V.y., Zhang, Z.-Y. & Weiss, S.J. Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L and S by human monocyte-derived macrophages. Proc. Natl. Acad. Sci. USA 92, 3849–3853 (1995).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5693 people with diabetes: a randomized placebo-controlled trial. Lancet 361, 2005–2013 (2003).

  36. Moreno, P.R. et al. Coronary composition and macrophage infiltration in atherectomy specimens from patients with diabetes mellitus. Circulation 102, 2180–2184 (2000).

    Article  PubMed  CAS  Google Scholar 

  37. Burke, A.P. et al. Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study. Arterioscler. Thromb. Vasc. Biol. 24, 1266–1271 (2004).

    Article  PubMed  CAS  Google Scholar 

  38. Pennathur, S. & Heinecke, J.W. Mechanisms for oxidative stress in diabetic cardiovascular disease. Antioxid. Redox Signal. 9, 955–969 (2007).

    Article  PubMed  CAS  Google Scholar 

  39. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5 and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Navab, M. et al. The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J. Lipid Res. 45, 993–1007 (2004).

    Article  PubMed  CAS  Google Scholar 

  41. Sangvanich, P., Mackness, B., Gaskell, S.J., Durrington, P. & Mackness, M. The effect of high-density lipoproteins on the formation of lipid/protein conjugates during in vitro oxidation of low-density lipoprotein. Biochem. Biophys. Res. Commun. 300, 501–506 (2003).

    Article  PubMed  CAS  Google Scholar 

  42. Getz, G.S. & Reardon, C.A. Diet and murine atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 26, 242–249 (2006).

    Article  PubMed  CAS  Google Scholar 

  43. Caslake, M.J. et al. Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase: a potential new risk factor for coronary artery disease. Atherosclerosis 150, 413–419 (2000).

    Article  PubMed  CAS  Google Scholar 

  44. Van Eck, M. et al. Bone marrow transplantation in apolipoprotein E–deficient mice. Effect of ApoE gene dosage on serum lipid concentrations, βVLDL catabolism, and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 17, 3117–3126 (1997).

    Article  PubMed  CAS  Google Scholar 

  45. Singer, A.G. et al. Interfacial kinetic and binding properties of the complete set of human and mouse groups I, II, V, X and XII secreted phospholipases A2 . J. Biol. Chem. 277, 48535–48549 (2002).

    Article  PubMed  CAS  Google Scholar 

  46. Smart, B.P. et al. Inhibition of the complete set of mammalian secreted phospholipases A2 by indole analogues: a structure-guided study. Bioorg. Med. Chem. 12, 1737–1749 (2004).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The superb animal husbandry of H. Profka is gratefully acknowledged. We greatly appreciate the input by M. Hurle into the design and confirmation of the Taqman probes and the advice and support related to immunofluorescence procedures of P. Crino. These studies were supported by funding from GlaxoSmithKline through an industry-academic alliance via the Alternative Drug Discovery Initiative with the University of Pennsylvania School of Medicine. M.H.G. is funded by US National Institutes of Health grant R37HL036235.

Author information

Authors and Affiliations

  1. Hospital of the University of Pennsylvania, 3400 Spruce Street, 9 Gates, Philadelphia, 19104, Pennsylvania, USA

    Robert L Wilensky, Emile R Mohler III, Damir Hamamdzic, Robert S Fenning, Daniel J Pelchovitz & Jisheng Yang

  2. Thomas Jefferson University, 1025 Walnut Street, Philadelphia, 19107, Pennsylvania, USA

    Yi Shi, LeFeng Zhang, Ping Zhang & Andrew Zalewski

  3. GlaxoSmithKline, 709 Swedeland Road

    Mark E Burgert, Jun Li, Bryan E Hoffman, Rosanna C Mirabile, Christine L Webb, Max C Walker, Andrew Zalewski & Colin H Macphee

  4. King of Prussia, 19406, Pennsylvania, USA

    Mark E Burgert, Jun Li, Bryan E Hoffman, Rosanna C Mirabile, Christine L Webb, Max C Walker, Andrew Zalewski & Colin H Macphee

  5. Division of Infection, Inflammation & Repair, Mail Point 825 Level F South, Southhampton General Hospital, Tremona Road, SO16 6YD, Southampton, UK

    Anthony Postle

  6. Departments of Chemistry and Biochemistry, Campus Box 351700, 36 Bagley Hall, University of Washington, Seattle, 98195, Washington, USA

    James G Bollinger & Michael H Gelb

Authors
  1. Robert L Wilensky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emile R Mohler III
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Damir Hamamdzic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark E Burgert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anthony Postle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert S Fenning
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. James G Bollinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bryan E Hoffman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Daniel J Pelchovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jisheng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Rosanna C Mirabile
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Christine L Webb
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. LeFeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michael H Gelb
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Max C Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Andrew Zalewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Colin H Macphee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.L.W., Y.S., E.R.M., III, M.C.W., A.Z. and C.H.M. conceived and designed the project and analyzed all data. R.L.W. and C.H.M. wrote the manuscript. Y.S., L.Z. and P.Z. performed studies on vascular inflammation. D.H., R.S.F., D.J.P., J.Y. and R.C.M. performed the histological and immunohistochemical analyses. M.E.B. performed statistical analysis. J.L. and B.E.H. performed the real-time PCR. A.P. performed the mass spectrometry. J.G.B. and M.H.G. determined selectivity of darapladib. C.L.W. carried out the analysis of Lp-PLA2 activity.

Corresponding author

Correspondence to Robert L Wilensky.

Ethics declarations

Competing interests

R.L.W., Y.S., E.R.M., III and A.P. are recipients of research grants from GlaxoSmithKline. M.E.B., B.E.H., R.C.M.,C.L.W., M.C.W., A.Z. and C.H.M. are employees of GlaxoSmithKline, the manufacturer of darapladib.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–3 and Supplementary Methods (PDF 256 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wilensky, R., Shi, Y., Mohler, E. et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 14, 1059–1066 (2008). https://doi.org/10.1038/nm.1870

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.1870

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