Skip to main content

Phospholipases in Cardiovascular Disease

  • Chapter
  • First Online:

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 10))

Abstract

Cardiovascular diseases comprise a frequent cause of morbidity and mortality in the modern world. Atherosclerosis, the most common pathophysiological process leading to cardiovascular disease, is a complex process involving many different pathways some of which are still under investigation. It has been shown that traditional risk factors are not sufficient in predicting cardiovascular events in the general population. Present research for the detection of substances that play a role in the atherogenic process has linked phospholipases with cardiovascular disease. Phospholipases, such as secretory phospholipase A2 and lipoprotein-associated phospholipase A2 (Lp-PLA2), have been considered as markers of vascular inflammation and could therefore play an important role in cardiovascular disease. Furthermore, it has been shown that pharmacological inhibition of Lp-PLA2 activity could exert beneficiary effects on the atherosclerotic process, offering a putative novel target for the management of these patients. This chapter summarizes current knowledge regarding various phospholipases and their role in atherogenesis. Studies involving these molecules will be investigated in order to enlighten the putative pathophysiologic mechanisms by which these proteins exert their effect on cardiovascular function. Additionally, the pharmacological interventions that influence phospholipase activity will be analyzed, proposing a putative new pharmacological approach for the treatment of atherosclerosis.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Castelli WP (1996) Lipids, risk factors and ischaemic heart disease. Atherosclerosis 124(Suppl):S1–S9

    Article  CAS  PubMed  Google Scholar 

  2. Rosenson RS, Gelb MH (2009) Secretory phospholipase A2: a multifaceted family of proatherogenic enzymes. Curr Cardiol Rep 11:445–451

    Article  PubMed  Google Scholar 

  3. Pruzanski W, Vadas P (1991) Phospholipase A2—a mediator between proximal and distal effectors of inflammation. Immunol Today 12:143–146

    CAS  PubMed  Google Scholar 

  4. Avoranta T, Sundstrom J, Korkeila E et al (2010) The expression and distribution of group IIA phospholipase A2 in human colorectal tumours. Virchows Arch 457:659–667

    Article  CAS  PubMed  Google Scholar 

  5. Dong Z, Liu Y, Scott KF et al (2010) Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer. Carcinogenesis 131:1948–1955

    Article  Google Scholar 

  6. Kugiyama K, Ota Y, Takazoe K et al (1999) Circulating levels of secretory type II phospholipase A2 predict coronary events in patients with coronary artery disease. Circulation 100:1280–1284

    Article  CAS  PubMed  Google Scholar 

  7. Kugiyama K, Ota Y, Kawano H et al (2000) Increase in plasma levels of secretory type II phospholipase A2 in patients with coronary spastic angina. Cardiovasc Res 47:159–165

    Article  CAS  PubMed  Google Scholar 

  8. Asano K, Okamoto S, Fukunaga K et al (1999) Cellular source(s) of platelet-activating-factor acetylhydrolase activity in plasma. Biochem Biophys Res Commun 261:511–514

    Article  CAS  PubMed  Google Scholar 

  9. Nakajima K, Murakami M, Yanoshita R et al (1997) Activated mast cells release extracellular type platelet-activating factor acetylhydrolase that contributes to autocrine inactivation of platelet-activating factor. J Biol Chem 272:19708–19713

    Article  CAS  PubMed  Google Scholar 

  10. Laine P, Kaartinen M, Penttila A et al (1999) Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation 99:361–369

    Article  CAS  PubMed  Google Scholar 

  11. Macphee CH, Moores KE, Boyd HF et al (1999) Lipoprotein-associated phospholipase A2, platelet-activating factor acetyl hydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochem J 338:479–487

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Tselepis AD, Chapman MJ (2002) Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet-activating factor acetyl hydrolase. Atheroscler Suppl 3:57–68

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Kolodgie FD, Burke AP, Skorija KS et al (2006) Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 26:2523–2529

    Article  CAS  PubMed  Google Scholar 

  15. Chen CH (2004) Platelet activating factor acetylhydrolase: is it good or bad for you? Curr Opin Lipidiol 15:337–341

    Article  CAS  Google Scholar 

  16. Hakkinen T, Luoma JS, Hiltunen MO et al (1999) Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, is expressed by macrophages in human and rabbit atherosclerotic lesions. Arterioscler Thromb Vasc Biol 19:2909–2917

    Article  CAS  PubMed  Google Scholar 

  17. Daniels LB, Laughlin GA, Sarno MJ et al (2008) Lipoprotein-associated phospholipase A2 is an independent predictor of incident coronary heart disease in an apparently healthy older population: the Rancho Bernardo Study. J Am Coll Cardiol 51:913–919

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Pillarisetti S, Alexander CW, Saxena U (2004) Atherosclerosis—new targets and therapeutics. Curr Med Chem Cardiovasc Hematol Agents 2:327–334

    Article  CAS  PubMed  Google Scholar 

  19. McCullough PA (2009) Darapladib and atherosclerotic plaque: should lipoprotein-associated phospholipase A2 be a therapeutic target? Curr Atheroscler Rep 11:334–337

    Article  CAS  PubMed  Google Scholar 

  20. Boekholdt SM, Keller TT, Wareham NJ et al (2005) Serum levels of type II secretory phospholipase A2 and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. Arterioscler Thromb Vasc Biol 25:839–846

    Article  CAS  PubMed  Google Scholar 

  21. Xin H, Chen ZY, Lv XB et al (2013) Serum secretory phospholipase A2-IIa (sPLA2-IIA) levels in patients surviving acute myocardial infarction. Eur Rev Med Pharmacol Sci 17:999–1004

    CAS  PubMed  Google Scholar 

  22. Shepherd J, Cobbe SM, Ford I et al (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333:1301–1307

    Article  CAS  PubMed  Google Scholar 

  23. Packard CJ, O’reilly DS, Caslake MJ et al (2000) Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. N Engl J Med 343:1148–1155

    Article  CAS  PubMed  Google Scholar 

  24. Ballantyne C, Hoogeveen R, Bank H et al (2004) Lipoprotein-associated phospholipase A2, high sensitive C-reactive protein and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation 109:837–842

    Article  CAS  PubMed  Google Scholar 

  25. Oei HH, van der Meer IM, Hofman A et al (2005) Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation 111:570–575

    Article  CAS  PubMed  Google Scholar 

  26. Koenig W, Khuseyinova N, Lowel H, Trischler G, Meisinger C (2004) Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany. Circulation 110:1903–1908

    Article  CAS  PubMed  Google Scholar 

  27. Tsimikas S, Willeit J, Knoflach M et al (2009) Lipoprotein-associated phospholipase A2 activity, ferritin levels, metabolic syndrome, and 10-year cardiovascular and non-cardiovascular mortality: results from the Bruneck study. Eur Heart J 30:107–115

    Article  CAS  PubMed  Google Scholar 

  28. Daniels LB, Laughlin GA, Sarno MJ et al (2008) Lipoprotein-associated phospholipase A2 is an independent predictor of incident coronary heart disease in an apparently healthy older population. The Rancho Bernardo Study. J Am Coll Cardiol 51:913–919

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Mockel M, Danne O, Muller R et al (2008) Development of an optimized biomarker strategy for early risk assessment of patients with acute coronary syndromes. Clin Chim Acta 393:103–109

    Article  PubMed  Google Scholar 

  30. Koenig W, Twardella D, Brenner H, Rothenbacher D (2006) Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscler Thromb Vasc Biol 26:1586–1593

    Article  CAS  PubMed  Google Scholar 

  31. Sabatine MS, Morrow DA, O’Donoghue M et al (2007) Prognostic utility of lipoprotein-associated phospholipase A2 for cardiovascular outcomes in patients with stable coronary artery disease. Arterioscler Thromb Vasc Biol 27:2463–2469

    Article  CAS  PubMed  Google Scholar 

  32. Rallidis LS, Tellis CC, Lekakis J et al (2012) Lipoprotein-associated phospholipase A(2) bound on high-density lipoprotein is associated with lower risk for cardiac death in stable coronary artery disease patients: a 3-year follow-up. J Am Coll Cardiol 60:2053–2060

    Article  CAS  PubMed  Google Scholar 

  33. Ridker PM, Danielson E, Fonseca F et al (2008) Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 359:2195–2207

    Article  CAS  PubMed  Google Scholar 

  34. Ikonomidis I, Lekakis JP, Nikolaou M et al (2008) Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation 117:2662–2669

    Article  CAS  PubMed  Google Scholar 

  35. Tomita Y, Kuwabara K, Furue S et al (2004) Effect of a selective inhibitor of secretory phospholipase A2, S-5920/LY315920Na, on experimental acute pancreatitis in rats. J Pharmacol Sci 96:144–1454

    Article  CAS  PubMed  Google Scholar 

  36. Bradley JD, Dmitrienko AA, Kivitz AJ et al (2005) A randomized, double-blinded, placebo-controlled clinical trial of LY333013, a selective inhibitor of group II secretory phospholipase A2, in the treatment of rheumatoid arthritis. J Rheumatol 32:417–423

    CAS  PubMed  Google Scholar 

  37. Zeiher BG, Steingrub J, Laterre PF et al (2005) PFLY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis. Crit Care Med 33:1741–1748

    Article  CAS  PubMed  Google Scholar 

  38. Leite JO, Vaishnav U, Puglisi M et al (2009) A-002 (Varespladib), a phospholipase A2 inhibitor, reduces atherosclerosis in guinea pigs. BMC Cardiovasc Disord 9:7

    Article  PubMed Central  PubMed  Google Scholar 

  39. Karakas M, Koenig W (2009) Varespladib methyl, an oral phospholipase A2 inhibitor for the potential treatment of coronary artery disease. IDrugs 12:585–592

    CAS  PubMed  Google Scholar 

  40. Suckling KE (2009) Phospholipase A2 inhibitors in the treatment of atherosclerosis: a new approach moves forward in the clinic. Expert Opin Investig Drugs 18:1425–1430

    Article  CAS  PubMed  Google Scholar 

  41. Caslake MJ, Packard CJ (2003) Lp-PLA2 and cardiovascular disease. Curr Opin Lipidol 14:347–352

    Article  CAS  PubMed  Google Scholar 

  42. Tsimihodimos V, Karabina SA, Tambaki AP et al (2002) Atorvastatin preferentially reduces LDL-associated platelet-activating factor acetyl hydrolase activity in dyslipidemias of type IIA and type IIB. Arterioscler Thromb Vasc Biol 22:306–311

    Article  CAS  PubMed  Google Scholar 

  43. Tsimihodimos V, Kakafika A, Tambaki AP et al (2003) Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity associated with apoB-containing lipoproteins. J Lipid Res 44:927–934

    Article  CAS  PubMed  Google Scholar 

  44. Riley RF, Corson MA (2009) Darapladib, a reversible lipoprotein-associated phospholipase A2 inhibitor, for the oral treatment of atherosclerosis and coronary artery disease. IDrugs 12:648–655

    CAS  PubMed  Google Scholar 

  45. Wilensky RL, Shi Y, Mohler ER et al (2008) Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 14:1059–1066

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Mohler ER, Ballantyne CM, Davidson MH et al (2008) 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 51:1632–1641

    Article  CAS  PubMed  Google Scholar 

  47. Serruys PW, García-García HM, Buszman P et al (2008) Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 118:1172–1182

    Article  CAS  PubMed  Google Scholar 

  48. White H, Held C, Stewart R et al (2010) Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease. Am Heart J 160:655–661

    Article  CAS  PubMed  Google Scholar 

  49. O’Donoghue ML, Braunwald E, White HD et al (2011) Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J 162:613–619

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ignatios Ikonomidis Ph.D., F.E.S.C. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Ikonomidis, I., Michalakeas, C.A. (2014). Phospholipases in Cardiovascular Disease. In: Tappia, P., Dhalla, N. (eds) Phospholipases in Health and Disease. Advances in Biochemistry in Health and Disease, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0464-8_4

Download citation

Publish with us

Policies and ethics