Current Atherosclerosis Reports

, Volume 12, Issue 1, pp 43–47 | Cite as

Recent Developments with Lipoprotein-Associated Phospholipase A2 Inhibitors

  • Ryan J. Chauffe
  • Robert L. Wilensky
  • Emile R. MohlerIII


Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a calcium-independent phospholipase A2 enzyme secreted by leukocytes and associated with circulating low-density lipoprotein and macrophages in atherosclerotic plaques. Until recently, the biological role of Lp-PLA2 in atherosclerosis was controversial, but now the preponderance of evidence demonstrates a proatherogenic role of this enzyme. Lp-PLA2 generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. These findings have opened the door to a potential novel therapeutic target, selective inhibition of Lp-LPA2. Recently, both animal models and human studies have shown that selective inhibition of Lp-PLA2 reduces plasma Lp-PLA2 activity, plaque area, and necrotic core area. This article reviews the most recent developments with Lp-PLA2 inhibitors.


Phospholipase Lipoprotein Atherosclerosis Myocardial infarction Atherothrombosis 


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Ross R: Atherosclerosis—an inflammatory disease. N Engl J Med 1999, 340:115–126.CrossRefPubMedGoogle Scholar
  2. 2.
    Hansson GK, Libby P: The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006, 6:508–519.CrossRefPubMedGoogle Scholar
  3. 3.
    Wilensky RL: Vulnerable plaque: scope of the problem. J Interv Cardiol 2008, 21:443–451.CrossRefPubMedGoogle Scholar
  4. 4.
    Cannon CP, Braunwald E, McCabe CH, et al.: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004, 350:1495–1504.CrossRefPubMedGoogle Scholar
  5. 5.
    Yusuf S, Sleight P, Pogue J, et al.: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000, 342:145–153.CrossRefPubMedGoogle Scholar
  6. 6.
    Steg PG, Bhatt DL, Wilson PW, et al.: One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007, 297:1197–1206.CrossRefPubMedGoogle Scholar
  7. 7.
    Zalewski A, Macphee C: Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol 2005, 25:923–931.CrossRefPubMedGoogle Scholar
  8. 8.
    Nambi V, Ballantyne CM: Lipoprotein-associated phospholipase A2: pathogenic mechanisms and clinical utility for predicting cardiovascular events. Curr Atheroscler Rep 2006, 8:374–381.CrossRefPubMedGoogle Scholar
  9. 9.
    MacPhee CH, Moores KE, Boyd HF, 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 1999, 338(Pt 2):479–487.CrossRefPubMedGoogle Scholar
  10. 10.
    Davis B, Koster G, Douet LJ, et al.: Electrospray ionization mass spectrometry identifies substrates and products of lipoprotein-associated phospholipase A2 in oxidized human low density lipoprotein. J Biol Chem 2008, 283:6428–6437.CrossRefPubMedGoogle Scholar
  11. 11.
    • Tsimikas S, Tsironis LD, Tselepis AD: New insights into the role of lipoprotein(a)-associated lipoprotein-associated phospholipase A2 in atherosclerosis and cardiovascular disease. Arterioscler Thromb Vasc Biol 2007, 27:2094–2099. This review focuses on the characteristics of Lp-PLA 2 ’s association with Lp(a) and its role in atherosclerosis development.CrossRefPubMedGoogle Scholar
  12. 12.
    Kougias P, Chai H, Lin PH, et al.: Lysophosphatidylcholine and secretory phospholipase A2 in vascular disease: mediators of endothelial dysfunction and atherosclerosis. Med Sci Monit 2006, 12:RA5–RA16.PubMedGoogle Scholar
  13. 13.
    Stafforini DM, McIntyre TM, Zimmerman GA, et al.: Platelet-activating factor acetylhydrolases. J Biol Chem 1997, 272:17895–17898.CrossRefPubMedGoogle Scholar
  14. 14.
    Henig NR, Aitken ML, Liu MC, et al.: Effect of recombinant human platelet-activating factor-acetylhydrolase on allergen-induced asthmatic responses. Am J Respir Crit Care Med 2000, 162(2 Pt 1):523–527.PubMedGoogle Scholar
  15. 15.
    Opal S, Laterre PF, Abraham E, et al.: Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial. Crit Care Med 2004, 32:332–341.CrossRefPubMedGoogle Scholar
  16. 16.
    Macphee CH, Nelson JJ, Zalewski A: Lipoprotein-associated phospholipase A2 as a target of therapy. Curr Opin Lipidol 2005, 16:442–446.CrossRefPubMedGoogle Scholar
  17. 17.
    Garza CA, Montori VM, McConnell JP, et al.: Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin Proc 2007, 82:159–165.CrossRefPubMedGoogle Scholar
  18. 18.
    Shi Y, Zhang P, Zhang L, et al.: Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses. Atherosclerosis 2007, 191:54–62.CrossRefPubMedGoogle Scholar
  19. 19.
    Carpenter KL, Challis IR, Arends MJ: Mildly oxidised LDL induces more macrophage death than moderately oxidised LDL: roles of peroxidation, lipoprotein-associated phospholipase A2 and PPARgamma. FEBS Lett 2003, 553:145–150.CrossRefPubMedGoogle Scholar
  20. 20.
    Gautier EL, Huby T, Witztum JL, et al.: Macrophage apoptosis exerts divergent effects on atherogenesis as a function of lesion stage. Circulation 2009, 119:1795–1804.CrossRefPubMedGoogle Scholar
  21. 21.
    Perez R, Balboa MA, Balsinde J: Involvement of group VIA calcium-independent phospholipase A2 in macrophage engulfment of hydrogen peroxide-treated U937 cells. J Immunol 2006, 176:2555–2561.PubMedGoogle Scholar
  22. 22.
    Aprahamian T, Rifkin I, Bonegio R, et al.: Impaired clearance of apoptotic cells promotes synergy between atherogenesis and autoimmune disease. J Exp Med 2004, 199:1121–1131.CrossRefPubMedGoogle Scholar
  23. 23.
    Kolodgie FD, Burke AP, Skorija KS, et al.: Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2006, 26:2523–2529.CrossRefPubMedGoogle Scholar
  24. 24.
    • Anderson JL: Lipoprotein-associated phospholipase A2: an independent predictor of coronary artery disease events in primary and secondary prevention. Am J Cardiol 2008, 101:23F–33F. This is an informative summary of studies evaluating the role of Lp-PLA2 as a biomarker of increased cardiovascular risk.CrossRefPubMedGoogle Scholar
  25. 25.
    •• Wilensky RL, Shi Y, Mohler ER 3rd, et al.: Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008, 14:1059–1066. This article demonstrates that selective inhibition of Lp-PLA 2 inhibited progression to advanced coronary atheroscelerostic lesions in a large animal model of complex coronary artery disease, confirming the important independent role of vascular inflammation in the development of high-risk coronary lesions.CrossRefPubMedGoogle Scholar
  26. 26.
    •• Mohler ER 3rd, Ballantyne CM, Davidson MH, et al.: The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2008, 51:1632–1641. This is a large-scale evaluation of darapladib’s effects on lipid levels, inflammation, and biomarkers of platelet activation. Key results include a reduction of interleukin-6 on treatment and no adverse effects on platelet function.CrossRefPubMedGoogle Scholar
  27. 27.
    •• Serruys PW, Garcia-Garcia HM, Buszman P, et al.: Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008, 118:1172–1182. This is the initial study evaluating potential antiatherogenic effects of darapladib in humans. The primary end point of plaque deformability determined via IVUS was not significant, although a reduction in necrotic core size was observed in darapladib-treated participants.CrossRefPubMedGoogle Scholar
  28. 28.
    Virmani R, Burke AP, Farb A, et al.: Pathology of the vulnerable plaque. J Am Coll Cardiol 2006, 47(8 Suppl):C13–C18.CrossRefPubMedGoogle Scholar
  29. 29.
    Filippatos TD, Gazi IF, Liberopoulos EN, et al.: The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis 2007, 193:428–437.CrossRefPubMedGoogle Scholar
  30. 30.
    Robins SJ, Collins D, Nelson JJ, et al.: Cardiovascular events with increased lipoprotein-associated phospholipase A(2) and low high-density lipoprotein-cholesterol: the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol 2008, 28:1172–1178.CrossRefPubMedGoogle Scholar
  31. 31.
    Kuvin JT, Dave DM, Sliney KA, et al.: Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol 2006, 98:743–745.CrossRefPubMedGoogle Scholar
  32. 32.
    Muhlestein JB, May HT, Jensen JR, et al.: The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J Am Coll Cardiol 2006, 48:396–401.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Ryan J. Chauffe
    • 1
  • Robert L. Wilensky
    • 2
  • Emile R. MohlerIII
    • 3
  1. 1.Pennsylvania HospitalPhiladelphiaUSA
  2. 2.Hospital of the University of PennsylvaniaPhiladelphiaUSA
  3. 3.Hospital of the University of PennsylvaniaPhiladelphiaUSA

Personalised recommendations