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Recent Developments with Lipoprotein-Associated Phospholipase A2 Inhibitors

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Abstract

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.

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References

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

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Wilensky RL: Vulnerable plaque: scope of the problem. J Interv Cardiol 2008, 21:443–451.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  6. Steg PG, Bhatt DL, Wilson PW, et al.: One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007, 297:1197–1206.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  13. Stafforini DM, McIntyre TM, Zimmerman GA, et al.: Platelet-activating factor acetylhydrolases. J Biol Chem 1997, 272:17895–17898.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  16. Macphee CH, Nelson JJ, Zalewski A: Lipoprotein-associated phospholipase A2 as a target of therapy. Curr Opin Lipidol 2005, 16:442–446.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  28. Virmani R, Burke AP, Farb A, et al.: Pathology of the vulnerable plaque. J Am Coll Cardiol 2006, 47(8 Suppl):C13–C18.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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Disclosure

Drs. Mohler and Wilensky have received grant support from GlaxoSmithKline, and Dr. Mohler is a consultant for GlaxoSmithKline. No other potential conflicts of interest relevant to this article were reported.

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Authors and Affiliations

  1. Pennsylvania Hospital, 1 Pine West, 800 Spruce Street, Philadelphia, PA, 19107, USA

    Ryan J. Chauffe

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

    Robert L. Wilensky

  3. Hospital of the University of Pennsylvania, 4th floor Penn Tower, 3400 Spruce Street, Philadelphia, PA, 19104, USA

    Emile R. Mohler III

Authors
  1. Ryan J. Chauffe
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  2. Robert L. Wilensky
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  3. Emile R. Mohler III
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Correspondence to Emile R. Mohler III.

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Chauffe, R.J., Wilensky, R.L. & Mohler, E.R. Recent Developments with Lipoprotein-Associated Phospholipase A2 Inhibitors. Curr Atheroscler Rep 12, 43–47 (2010). https://doi.org/10.1007/s11883-009-0076-9

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