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Future Role for Selective Phospholipase A2 Inhibitors in the Prevention of Atherosclerotic Cardiovascular Disease

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References

  1. Shah PK. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2008 doi:10.1007/s10557-008-6147-2.

  2. Boyanovsky BB, Webb NR. Biology of secretory phospholipase A2. Cardiovasc Drugs Ther 2008 doi:10.1007/s10557-008-6134-7.

  3. Stafforini DM. Biology of platelet-activating factor acetylhydrolase (PAF-AH, lipoprotein associated phospholipase A2). Cardiovasc Drugs Ther 2008 doi:10.1007/s10557-008-6133-8.

  4. Burke JE, Dennis EA. Phospholipase A2 biochemistry. Cardiovasc Drugs Ther 2008 doi:10.1007/s10557-008-6132-9.

  5. Menschikowski M, Kasper M, Lattke P, Schiering A, Schiefer S, Stockinger H, et al. Secretory group II phospholipase A2 in human atherosclerotic plaques. Atherosclerosis 1995;118:173–81.

    Article  PubMed  CAS  Google Scholar 

  6. Elinder LS, Dumitrescu A, Larsson P, Hedin U, Frostegard J, Claesson HE. Expression of phospholipase A2 isoforms in human normal and atherosclerotic arterial wall. Arterioscler Thromb Vasc Biol 1997;17:2257–63.

    PubMed  CAS  Google Scholar 

  7. Hurt-Camejo E, Andersen S, Standal R, Rosengren B, Sartipy P, Stadberg E, et al. Localization of nonpancreatic secretory phospholipase A2 in normal and atherosclerotic arteries: activity of the isolated enzyme on low-density lipoproteins. Arterioscler Thromb Vasc Biol 1997;17:300–9.

    PubMed  CAS  Google Scholar 

  8. Rosengren B, Peilot H, Umaerus M, Jonsson-Rylander AC, Mattsson-Hulten L, Hallberg C, et al. Secretory phospholipase A2 group V: lesion distribution, activation by arterial proteoglycans, and induction in aorta by a western diet. Arterioscler Thromb Vasc Biol 2006;26:1579–85.

    Article  PubMed  CAS  Google Scholar 

  9. Bostrom MA, Boyanovsky BB, Jordan CT, Wadsworth MP, Taatjes DJ, De Beer FC, et al. Group V secretory phospholipase A2 promotes atherosclerosis: evidence from genetically altered mice. Arterioscler Thromb Vasc Biol 2007;27:600–6.

    Article  PubMed  CAS  Google Scholar 

  10. Hanasaki K, Yamada K, Yamamoto S, Ishimoto Y, Saiga A, Ono T, et al. Potent modification of low density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formation. J Biol Chem 2002;277:29116–24.

    Article  PubMed  CAS  Google Scholar 

  11. Ivandic B, Castellani LW, Wang XP, Qiao JH, Mehrabian M, Navab M, et al. Role of group II secretory phospholipase A2 in atherosclerosis : 1. Increased atherogenesis and altered lipoproteins in transgenic mice expressing group IIA phospholipase A2. Arterioscler Thromb Vasc Biol 1999;19:1284–90.

    PubMed  CAS  Google Scholar 

  12. Sartipy P, Camejo G, Svensson L, Hurt-Camejo E. Phospholipase A2 modification of low density lipoproteins forms small high density particles with increased affinity for proteoglycans and glycosaminoglycans. J Biol Chem 1999;274:25913–20.

    Article  PubMed  CAS  Google Scholar 

  13. Karabina SA, Brocheriou I, Le Naour G, Agrapart M, Durand H, Gelb M, et al. Atherogenic properties of LDL particles modified by human group X secreted phospholipase A2 on human endothelial cell function. FASEB J 2006;20:2547–9.

    Article  PubMed  CAS  Google Scholar 

  14. Wooton-Kee CR, Boyanovsky BB, Nasser MS, De Villiers WJ, Webb NR. Group V sPLA2 hydrolysis of low-density lipoprotein results in spontaneous particle aggregation and promotes macrophage foam cell formation. Arterioscler Thromb Vasc Biol 2004;24:762–7.

    Article  PubMed  CAS  Google Scholar 

  15. Pruzanski W, Lambeau L, Lazdunsky M, Cho W, Kopilov J, Kuksis A. Differential hydrolysis of molecular species of lipoprotein phosphatidylcholine by groups IIA, V and X secretory phospholipases A2. Biochim Biophys Acta 2005;1736:38.

    PubMed  CAS  Google Scholar 

  16. Flood C, Gustafsson M, Pitas RE, Arnaboldi L, Walzem RL, Boren J. Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100. Arterioscler Thromb Vasc Biol 2004;24:564–70.

    Article  PubMed  CAS  Google Scholar 

  17. Kleinman Y, Krul ES, Burnes M, Aronson W, Pfleger B, Schonfeld G. Lipolysis of LDL with phospholipase A2 alters the expression of selected apoB-100 epitopes and the interaction of LDL with cells. J Lipid Res 1988;29:729–43.

    PubMed  CAS  Google Scholar 

  18. Hakala JK, Oorni K, Pentikainen MO, Hurt-Camejo E, Kovanen PT. Lipolysis of LDL by human secretory phospholipase A2 induces particle fusion and enhances the retention of LDL to human aortic proteoglycans. Arterioscler Thromb Vasc Biol 2001;21:1053–8.

    PubMed  CAS  Google Scholar 

  19. Ghesquiere SA, Gijbels MJ, Anthonsen M, Van Gorp PJ, Van Der Made I, Johansen B, et al. Macrophage-specific overexpression of group IIA sPLA2 increases atherosclerosis and enhances collagen deposition. J Lipid Res 2005;46:201–10.

    Article  PubMed  CAS  Google Scholar 

  20. Jonsson-Rylander AC, Lundin S, Rosengren B, Pettersson C, Hurt-Camejo E. Role of secretory phospholipases in atherogenesis. Curr Atheroscler Rep 2008;10:252–9.

    Article  PubMed  CAS  Google Scholar 

  21. Hartford M, Wiklund O, Hulten LM, Perers E, Person A, Herlitz J, et al. CRP, interleukin-6, secretory phospholipase A2 group IIA, and intercellular adhesion molecule-1 during the early phase of acute coronary syndromes and long-term follow-up. Int J Cardiol 2006;108:55–62.

    Article  PubMed  Google Scholar 

  22. Hurt-Camejo E, Camejo G, Peilot H, Oorni K, Kovanen P. Phospholipase A2 in vascular disease. Circ Res 2001;89:298–304.

    Article  PubMed  CAS  Google Scholar 

  23. Bäck M. Leukotriene signaling in atherosderosis and ischemia. Cardiovasc Drugs Ther 2008 doi:10.1007/s10557-008-6140-9.

  24. Zalewski A, Macphee C. Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler Thromb Vasc Biol 2005;25:923–31.

    Article  PubMed  CAS  Google Scholar 

  25. Mangin EL Jr, Kugiyama K, Nguy JH, Kerns SA, Henry PD. Effects of lysolipids and oxidatively modified low density lipoprotein on endothelium-dependent relaxation of rabbit aorta. Circ Res 1993;72:161–6.

    PubMed  CAS  Google Scholar 

  26. Hakkinen T, Luoma JS, Hiltunen MO, Macphee CH, Milliner KJ, Patel L, et al. Lipoprotein-associated phospholipase a(2), platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol 1999;19:2909–17.

    PubMed  CAS  Google Scholar 

  27. Marathe GK, Harrison KA, Murphy RC, Prescott SM, Zimmerman GA, McIntyre TM. Bioactive phospholipid oxidation products. Free Radic Biol Med 2000;28:1762–70.

    Article  PubMed  CAS  Google Scholar 

  28. Oslund RC, Cermak N, Gelb MH. Highly specific and broadly potent inhibitors of mammalian secreted phospholipases A2. J Med Chem 2008;51:4708–14.

    Article  PubMed  CAS  Google Scholar 

  29. Thommesen L, Sjursen W, Gasvik K, Hanssen W, Brekke OL, Skattebol L, et al. Selective inhibitors of cytosolic or secretory phospholipase A2 block TNF-induced activation of transcription factor nuclear factor-kappaB and expression of ICAM-1. J Immunol 1998;161:3421–30.

    PubMed  CAS  Google Scholar 

  30. Rosenson RS, Hislop C, Waters D, Mcconnell D, Elliot M, Stasiv Y. Effects of a selective inhibitor of secretory phospholipase A2 on low density lipoproteins and inflammatory pathways. Presented at ACC 2008, March 29–April 1 2008.

  31. De Graaf J, Hak-Lemmers HL, Hectors MP, Demacker PN, Hendriks JC, Stalenhoef AF. Enhanced susceptibility to in vitro oxidation of the dense low density lipoprotein subfraction in healthy subjects. Arterioscler Thromb 1991;11:298–306.

    PubMed  Google Scholar 

  32. Chang MY, Tsoi C, Wight TN, Chait A. Lysophosphatidylcholine regulates synthesis of biglycan and the proteoglycan form of macrophage colony stimulating factor. Arterioscler Thromb Vasc Biol 2003;23:809–15.

    Article  PubMed  CAS  Google Scholar 

  33. Benitez S, Camacho M, Arcelus R, Vila L, Bancells C, Ordonez-Llanos J, et al. Increased lysophosphatidylcholine and non-esterified fatty acid content in LDL induces chemokine release in endothelial cells: relationship with electronegative LDL. Atherosclerosis 2004;177:299–305.

    PubMed  CAS  Google Scholar 

  34. PLASMA trial. Phospholipase levels and serological markers of atherosclerosis: a dose-response clinical pharmacology study of A-002 in subjects with stable coronary artery disease. Clinicaltrialsgov Identifier: NCT00455546 Sponsored by Anthera Pharmaceuticals

  35. Balboa MA, Balsinde J, Winstead MV, Tischfield J, Dennis E. Novel group V phospholipase A2 involved in arachidonic acid mobilization in murine P388D1 macrophages. J Biol Chem 1996;271:32381–4.

    Article  PubMed  CAS  Google Scholar 

  36. Trias J, Fraser H, Hislop C. Prevention of atherosclerosis by sPLA2 inhibitor in a mouse model. Inflamm Res 2007;56:S384.

    Google Scholar 

  37. Shaposhnik Z, Wang X, Trias J, Fraser H, Lusis AJ. The synergistic inhibition of atherogenesis in apoE−/− mice between pravastatin and the sPLA2 inhibitor varespladib (A-002). Presented at ATVB 2008, April 16–18 2008.

  38. Nijmeijer R, Lagrand WK, Baidoshvili A, Lubbers YT, Hermens WT, Meijer CJ, et al. Secretory type II phospholipase A2 binds to ischemic myocardium during myocardial infarction in humans. Cardiovasc Res 2002;53:138–46.

    Article  PubMed  CAS  Google Scholar 

  39. Nijmeijer R, Lagrand WK, Visser CA, Meijer CJLM, Niessen HWM, Hack CE. CRP, a major culprit in complement-mediated tissue damage in acute myocardial infarction? Int Immunopharmacol 2001;1:403–14.

    Article  PubMed  CAS  Google Scholar 

  40. Fujioka D, Saito Y, Kobayashi T, Yano T, Tezuka H, Ishimoto Y, et al. Reduction in myocardial ischemia/reperfusion injury in group X secretory phospholipase A2-deficient mice. Circulation 2008;117:2977–85.

    Article  PubMed  CAS  Google Scholar 

  41. Koenig W, Khuseyinova N. Lipoprotein-associated and secretory phospholipase A2 in cardiovascular disease: the epidemiological evidence. Cardiovasc Drugs Ther 2008 doi:10.1007/s10557-008-6135-6.

  42. Kugiyama K, Ota Y, Takazoe K, Moriyama Y, Kawano H, Miyao Y, et al. Circulating levels of secretory type II phospholipase A2 predict coronary events in patients with coronary artery disease. Circulation 1999;100:1280–4.

    PubMed  CAS  Google Scholar 

  43. Liu PY, Li YH, Tsai WC, Chao TH, Tsai LM, Wu HL, et al. Prognostic value and the changes of plasma levels of secretory type II phospholipase A2 in patients with coronary artery disease undergoing percutaneous coronary intervention. Eur Heart J 2003;24:1824–32.

    Article  PubMed  CAS  Google Scholar 

  44. Kugiyama K, Ota Y, Sugiyama S, Kawano H, Doi H, Soejima H, et al. Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectoris. Am J Cardiol 2000;86:718–22.

    Article  PubMed  CAS  Google Scholar 

  45. Porela P, Pulkki K, Voipio-Pulkki LM, Pettersson K, Leppänen V, Nevalainen TJ. Level of circulating phospholipase A2 in prediction of the prognosis of patients with suspected myocardial infarction. Basic Res Cardiol 2000;95:413–7.

    Article  PubMed  CAS  Google Scholar 

  46. Mallat Z, Benessiano J, Simon T, Ederhy S, Sebella-Arguelles C, Cohen A, et al. Circulating secretory phospholipase A2 activity and risk of incident coronary events in healthy men and women: the EPIC-Norfolk study. Arterioscler Thromb Vasc Biol 2007;27:1177–83.

    Article  PubMed  CAS  Google Scholar 

  47. Tew DG, Boyd HF, Ashman S, Theobald C, Leach CA. Mechanism of inhibition of LDL phospholipase A2 by monocyclic-beta-lactams. Burst kinetics and the effect of stereochemistry. Biochemistry 1998;37:10087–93.

    Article  PubMed  CAS  Google Scholar 

  48. Mohler ER III, Ballantyne CM, Davidson MH, Hanefeld M, Ruilope LM, Johnson JL, 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;51:1632–41.

    Article  PubMed  CAS  Google Scholar 

  49. Rosenson RS, Vracar-Grabar M, Helenowski I. Lipoprotein associated phospholipase A2 inhibition reduces generation of oxidized fatty acids. Cardiovasc Drugs Ther 2008;22:55–8.

    Article  PubMed  CAS  Google Scholar 

  50. Macphee CH, Moores KE, Boyd HF, Dhanak D, Ife RJ, Leach CA, 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;338:479–87.

    Article  PubMed  CAS  Google Scholar 

  51. Carpenter KL, Dennis IF, Challis IR, Osborn DP, Macphee CH, Leake DS, et al. Inhibition of lipoprotein-associated phospholipase A2 diminishes the death-inducing effects of oxidised LDL on human monocyte-macrophages. FEBS Lett 2001;505:357–63.

    Article  PubMed  CAS  Google Scholar 

  52. Shi Y, Zhang P, Zhang L, Osman H, Mohler ER III, Macphee C, et al. Role of lipoprotein-associated phospholipase A2 in leukocyte activation and inflammatory responses. Atherosclerosis 2007;191:54–62.

    Article  PubMed  CAS  Google Scholar 

  53. Wilensky RL, Shi Y, Zalewski A, Mohler E III, Hamamdzic D, Li J, et al. A selective inhibitor of Lp-PLA2, reduces coronary atherosclerosis in diabetic, hypercholesterolemic swine. AHA Abstact 2007;116:II_33.

    Google Scholar 

  54. Johnson A, Zalewski A, Janmohamed S, Sawyer J, Rolfe T, Staszkiewicz W, et al. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, an emerging CV risk marker, can be inhibited in atherosclerotic lesions and plasma by novel pharmacologic intervention: the results of a multicenter clincal study. Circulation 2004;110:111–590.

    Google Scholar 

  55. Zhang P, Zhang L, Carabasi A, Diehl J, Dimuzio P, Dimatteo C, et al. Oxidized LDL-induced upregulation of IL-18 in monocytes/macrophages is modulated by lipoprotein-associated phospholipase A2—potential mechanism of inflammatory burden in atherosclerosis. AHA Abstact 2006;114:II_24.

    Google Scholar 

  56. Shi Y, Zalewski A, Macphee C, Dawson M. Selective inhibitor of lipoprotein-associated phospholipase A2 attenuates markers of plaque vulnerability in humans. AHA Abstact 2007;116:II_108.

    Google Scholar 

  57. Serruys PW, Garcia-Garcia HM, Buszman P, Erne P, Verheye S, Aschermann M, et al. Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008;118:1172–82.

    Article  PubMed  CAS  Google Scholar 

  58. Divchev D, Grothusen C, Luchtefeld M, Thoenes M, Onono F, Koch R, et al. Impact of a combined treatment of angiotensin II type 1 receptor blockade and 3-hydroxy-3-methyl-glutaryl-CoA-reductase inhibition on secretory phospholipase A2-type IIA and low density lipoprotein oxidation in patients with coronary artery disease. Eur Heart J 2008;29:1956–65.

    Article  PubMed  CAS  Google Scholar 

  59. Muhlestein JB, May HT, Jensen JR, Horne BD, Lanman RB, Lavasani F, et al. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIAbetes and COmbined lipid therapy Regimen (DIACOR) study. J Am Coll Cardiol 2006;48:396–401.

    Article  PubMed  CAS  Google Scholar 

  60. Tsimihodimos V, Kakafika A, Tambaki AP, Bairaktari E, Chapman MJ, Elisaf M, et al. Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity associated with apoB-containing lipoproteins. J Lipid Res 2003;44:927–34.

    Article  PubMed  CAS  Google Scholar 

  61. Tsimihodimos V, Kostoula A, Kakafika A, Bairaktari E, Tselepis AD, Mikhailidis DP, et al. Effect of fenofibrate on serum inflammatory markers in patients with high triglyceride values. J Cardiovasc Pharmacol Ther 2004;9:27–33.

    Article  PubMed  CAS  Google Scholar 

  62. Filippatos TD, Gazi IF, Liberopoulos EN, Athyros VG, Elisaf MS, Tselepis AD, 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;193:428–37.

    Article  PubMed  CAS  Google Scholar 

  63. Tambaki AP, Rizos E, Tsimihodimos V, Tselepis AD, Elisaf M. Effects of antihypertensive and hypolipidemic drugs on plasma and high-density lipoprotein-associated platelet activating factor-acetylhydrolase activity. J Cardiovasc Pharmacol Ther 2004;9:91–5.

    Article  PubMed  CAS  Google Scholar 

  64. Rosenson RS. Fenofibrate reduces lipoprotein associated phospholipase A2 mass and oxidative lipids in hypertriglyceridemic subjects with the metabolic syndrome. Am Heart J 2008;155:499.e9–.e16.

    Article  Google Scholar 

  65. Robins SJ, Collins D, Nelson JJ, Bloomfield HE, Asztalos BF. Cardiovascular events with increased lipoprotein-associated phospholipase A2 and low high-density lipoprotein-cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Arterioscler Thromb Vasc Biol 2008;28:1172–8.

    Article  PubMed  CAS  Google Scholar 

  66. Kuvin JT, Dave DM, Sliney KA, Mooney P, Patel AR, Kimmelstiel CD, 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;98:743–5.

    Article  PubMed  CAS  Google Scholar 

  67. Schaefer EJ, Mcnamara JR, Asztalos BF, Tayler T, Daly JA, Gleason JL, et al. Effects of atorvastatin versus other statins on fasting and postprandial c-reactive protein and lipoprotein-associated phospholipase A2 in patients with coronary heart disease versus control subjects. Am J Cardiol 2005;95:1025–32.

    Article  PubMed  CAS  Google Scholar 

  68. Wiklund O, Mattsson-Hulten L, Hurt-Camejo E, Oscarsson J. Effects of simvastatin and atorvastatin on inflammation markers in plasma. J Intern Med. 2002;251:338–47.

    Article  PubMed  CAS  Google Scholar 

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    Robert S. Rosenson

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Rosenson, R.S. Future Role for Selective Phospholipase A2 Inhibitors in the Prevention of Atherosclerotic Cardiovascular Disease. Cardiovasc Drugs Ther 23, 93–101 (2009). https://doi.org/10.1007/s10557-008-6148-1

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