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Current Cardiology Reviews


ISSN (Print): 1573-403X
ISSN (Online): 1875-6557

Review Article

Phospholipase A2 is an Inflammatory Predictor in Cardiovascular Diseases: Is there any Spacious Room to Prove the Causation?

Author(s): Anwar Santoso*, Teuku Heriansyah and Mohammad S. Rohman

Volume 16 , Issue 1 , 2020

Page: [3 - 10] Pages: 8

DOI: 10.2174/1573403X15666190531111932

Price: $65


Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme family of phospholipase A2 produced by the inflammatory cell in atherosclerotic plaque. It is transported in the circulation, attached mainly to low-density lipoprotein-cholesterol (LDL-C). It hydrolyzes glycerophospholipids particularly fatty acids at the sn-2 position and produces numerous bioactive lipids; and leads to endothelial dysfunction, atherosclerotic plaque inflammation, and development of the necrotic core in plaques.

There are two kinds of phospholipase A2, namely: secretory phospholipase A2 (sPLA2) and Lp- PLA2. They are deemed as evolving predictors of cardiovascular disease (CVD) risk in hospitaland population-based studies, including healthy subjects, acute coronary syndromes (ACS) and patients with CVD. Unfortunately, Lp-PLA2 inhibitor (darapladib) and s-PLA2 inhibitor (varespladib methyl) failed to prove to lower the risk of composite CVD mortality, myocardial infarction and stroke in those with stable CVD and ACS.

Herein, we describe the explanation based on the existing data why there is still a discrepancy among them. So, it highlights the opinion that phospholipase A2 is merely the inflammatory biomarkers of CVD and playing an important role in atherosclerosis. Further, there is more spacious room to prove the causation.

Keywords: Lipoprotein-associated phospholipase A2, LDL-C, cardiovascular disease, acute coronary syndromes, myocardial infarction, atherosclerosis.

Graphical Abstract
Yang ZJ, Liu J, Ge JP, Chen L, Zhao ZG, Yang WY. Prevalence of cardiovascular disease risk factor in the Chinese population: the 2007-2008 China National Diabetes and Metabolic Disorders Study. Eur Heart J 2012; 33(2): 213-20.
[] [PMID: 21719451]
Alshamiri M, Ghanaim MMA, Barter P, et al. Expert opinion on the applicability of dyslipidemia guidelines in Asia and the Middle East. Int J Gen Med 2018; 11: 313-22.
[] [PMID: 30050317]
Alsheikh-Ali AA, Omar MI, Raal FJ, et al. Cardiovascular risk factor burden in Africa and the Middle East: the Africa Middle East Cardiovascular Epidemiological (ACE) study. PLoS One 2014; 9(8)e102830
[] [PMID: 25090638]
Gao F, Zhou YJ, Hu DY, et al. Contemporary management and attainment of cholesterol targets for patients with dyslipidemia in China. PLoS One 2013; 8(4)e47681
[] [PMID: 23593110]
Hartley A, Dorian H, Khamis R. Oxidized and anti-oxidized LDL antibodies in atherosclerosis - Novel insights and future direction in diagnosis and therapy. Trends Cardiovasc Med 2018; S1050- 1738(18): 30083-5.
Santoso A, Kaniawati M, Bakri S, Yusuf I. Secretory phospholipase A2 is associated with the odds of acute coronary syndromes through elevation of serum amyloid-A protein. Int J Angiol 2013; 22(1): 49-54.
[] [PMID: 24436584]
Garg PK, Norby FL, Polfus LM, et al. Lipoprotein-associated phospholipase A2 and risk of incident peripheral arterial disease: Findings from The Atherosclerosis Risk in Communities study (ARIC). Atherosclerosis 2018; 268: 12-8.
[] [PMID: 29169030]
Li D, Zhao L, Yu J, et al. Lipoprotein-associated phospholipase A2 in coronary heart disease: Review and meta-analysis. Clin Chim Acta 2017; 465: 22-9.
[] [PMID: 27956130]
Thompson A, Gao P, Orfei L, et al. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 2010; 375(9725): 1536-44.
[] [PMID: 20435228]
Wilensky RL, Shi Y, Mohler ER III, et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med 2008; 14(10): 1059-66.
[] [PMID: 18806801]
Johnson JL, Shi Y, Snipes R, et al. Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial. PLoS One 2014; 9(2)e89034
Rosenson RS, Hislop C, McConnell D, et al. PLASMA Investigators. Effects of 1-H-indole-3-glyxoamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomized, placebo-controlled trial. Lancet 2009; 373(9664): 649-58.
Rosenson RS, Hislop C, Elliott M, Stasiv Y, Goulder M, Waters D. Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients. J Am Coll Cardiol 2010; 56(14): 1079-88.
[] [PMID: 20863951]
White HD, Held C, Stewart R, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med 2014; 370(18): 1702-11.
[] [PMID: 24678955]
Nicholls SJ, Kastelein JJP, Schwartz GG, et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. JAMA 2014; 311(3): 252-62.
[] [PMID: 24247616]
Rosenson RS, Hurt-Camejo E. Phospholipase A2 enzymes and the risk of atherosclerosis. Eur Heart J 2012; 33(23): 2899-909.
[] [PMID: 22802388]
Rana JS, Arsenault BJ, Després J-P, et al. Inflammatory biomarkers, physical activity, waist circumference, and risk of future coronary heart disease in healthy men and women. Eur Heart J 2011; 32(3): 336-44.
[] [PMID: 19224930]
Hatoum IJ, Cook NR, Nelson JJ, Rexrode KM, Rimm EB. Lipoprotein-associated phospholipase A2 activity improves risk discrimination of incident coronary heart disease among women. Am Heart J 2011; 161(3): 516-22.
[] [PMID: 21392606]
Sun CQ, Zhong CY, Sun WW, et al. Elevated Type II Secretory Phospholipase A2 Increases the Risk of Early Atherosclerosis in Patients with Newly Diagnosed Metabolic Syndrome. Sci Rep 2016; 6: 34929.
[] [PMID: 27941821]
Ge PC, Chen ZH, Pan RY, et al. Synergistic Effect of Lipoprotein-Associated Phospholipase A2 with Classical Risk Factors on Coronary Heart Disease: A Multi-Ethnic Study in China. Cell Physiol Biochem 2016; 40(5): 953-68.
[] [PMID: 27941334]
Winkler K, Winkelmann BR, Scharnagl H, et al. Platelet-activating factor acetylhydrolase activity indicates angiographic coronary artery disease independently of systemic inflammation and other risk factors: the Ludwigshafen Risk and Cardiovascular Health Study. Circulation 2005; 111(8): 980-7.
[] [PMID: 15710755]
Brilakis ES, McConnell JP, Lennon RJ, Elesber AA, Meyer JG, Berger PB. Association of lipoprotein-associated phospholipase A2 levels with coronary artery disease risk factors, angiographic coronary artery disease, and major adverse events at follow-up. Eur Heart J 2005; 26(2): 137-44.
[] [PMID: 15618069]
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(11): 2523-9.
[] [PMID: 16960105]
Maiolino G, Bisogni V, Rossitto G, Rossi GP. Lipoprotein-associated phospholipase A2 prognostic role in atherosclerotic complications. World J Cardiol 2015; 7(10): 609-20.
[] [PMID: 26516415]
Kheirandish-Gozal L, Philby MF, Qiao Z, Khalyfa A, Gozal D. Endothelial dysfunction in children with obstructive sleep apnea is associated with elevated lipoprotein-associated phospholipase A2 plasma activity levels. J Am Heart Assoc 2017; 6(2)e004923
[] [PMID: 28183716]
Yang EH, McConnell JP, Lennon RJ, et al. Lipoprotein-associated phospholipase A2 is an independent marker for coronary endothelial dysfunction in humans. Arterioscler Thromb Vasc Biol 2006; 26(1): 106-11.
[ 87296.ab] [PMID: 16239595]
Tousoulis D, Papageorgiou N, Androulakis E, Stefanadis C. Lp-PLA2--a novel marker of atherosclerosis: to treat or not to treat? Int J Cardiol 2013; 165(2): 213-6.
[] [PMID: 23103134]
Fleming I, Mohamed A, Galle J, et al. Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKCalpha. Cardiovasc Res 2005; 65(4): 897-906.
[] [PMID: 15721870]
Li J, Wang H, Tian J, Chen B, Du F. Change in lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndrome. Medicine (Baltimore) 2018; 97(28)e11517
[] [PMID: 29995820]
Wang C, Fang X, Hua Y, et al. Lipoprotein-associated phospholipase A2 and risk of carotid atherosclerosis and cardiovascular events in community-based older adults in China. Angiology 2018; 69(1): 49-58.
[] [PMID: 28429599]
Liu H, Yao Y, Wang Y, et al. Association between high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 and carotid atherosclerosis: A cross-sectional study. J Cell Mol Med 2018; 22(10): 5145-50.
[] [PMID: 30094934]
Tian Y, Jia H, Li S, et al. The associations of stroke, transient ischemic attack, and stroke-related recurrent vascular events with Lipoprotein-associated phospholipase A2. A systematic review and meta-analysis. Medicine 2017; 96: 51: e9413.
Garg PK, Jorgensen NW, McClelland RL, et al. Lipoprotein-associated phospholipase A2 and risk of incident peripheral arterial disease in a multi-ethnic cohort: The Multi-Ethnic Study of Atherosclerosis. Vasc Med 2017; 22(1): 5-12.
[] [PMID: 28215109]
De Stefano A, Mannucci L, Tamburi F, et al. Lp-PLA2, a new biomarker of vascular disorders in metabolic diseases. Int J Immunopathol Pharmacol 2019.332058738419827154
[] [PMID: 30706739]
Siddiqui MK, Kennedy G, Carr F, et al. Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study. Diabetologia 2018; 61(6): 1344-53.
Lin XH, Xu MT, Tang JY, et al. Effect of intensive insulin treatment on plasma levels of lipoprotein-associated phospholipase A2 and secretory phospholipase A2 in patients with newly diagnosed type 2 diabetes. Lipids Health Dis 2016; 15(1): 203.
[] [PMID: 27881128]
Mattina A, Rosenbaum D, Bittar R, et al. Lipoprotein-associated phospholipase A2 activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia. Nutr Metab Cardiovasc Dis 2018; 28(5): 517-23.
[] [PMID: 29525223]
Tjoelker LW, Wilder C, Eberhardt C, et al. Anti-inflammatory properties of a platelet-activating factor acetylhydrolase. Nature 1995; 374(6522): 549-53.
[] [PMID: 7700381]
Kono N, Arai H. Platelet-activating factor acetylhydrolase: an overview and update. BBA – Molecular and Cell Biology of Lipids 2018.
Rosenson RS. Lp-PLA(2) and risk of atherosclerotic vascular disease. Lancet 2010; 375(9725): 1498-500.
[] [PMID: 20435213]
Rosenson RS. Physiochemically modified apolipoprotein B-containing lipoproteins and the risk of cardiovascular disease. J Intern Med 2010; 268(4): 316-9.
[] [PMID: 21050285]
Tselepis AD, Dentan C, Karabina SA, Chapman MJ, Ninio E. PAF-degrading acetylhydrolase is preferentially associated with dense LDL and VHDL-1 in human plasma. Catalytic characteristics and relation to the monocyte-derived enzyme. Arterioscler Thromb Vasc Biol 1995; 15(10): 1764-73.
[ 10.1161/01.ATV.15.10.1764] [PMID: 7583554]
Tjoelker LW, Eberhardt C, Unger J, et al. Plasma platelet-activating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad. J Biol Chem 1995; 270(43): 25481-7.
[] [PMID: 7592717]
Samanta U, Bahnson BJ. Crystal structure of human plasma platelet-activating factor acetylhydrolase: structural implication to lipoprotein binding and catalysis. J Biol Chem 2008; 283(46): 31617-24.
[] [PMID: 18784071]
Cao J, Hsu YH, Li S, Woods VL, Dennis EA. Lipoprotein-associated phospholipase A(2) interacts with phospholipid vesicles via a surface-disposed hydrophobic α-helix. Biochemistry 2011; 50(23): 5314-21.
[] [PMID: 21553808]
Tselepis AD, John Chapman M. Inflammation, bioactive lipids, and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase. Atheroscler Suppl 2002; 3: 57-68.
Guerra R, Zhao BR, Mooser V, Stafforini D, Johnston JM, Cohen JC. Determinants of plasma-activating acetylhydrolase: heritability and relationship to plasma proteins. J Lipid Res 1997; 38: 2281-8.
[PMID: 9392426]
Schnabel R, Dupuis J, Larson MG, et al. Clinical and genetic factors associated with lipoprotein-associated phospholipase A2 in the Framingham Heart Study. Atherosclerosis 2009; 204(2): 601-7.
[] [PMID: 19135199]
Brilakis ES, Khera A, McGuire DK, et al. Influence of race and sex on lipoprotein-associated phospholipase A2 levels: observations from the Dallas Heart Study. Atherosclerosis 2008; 199(1): 110-5.
[PMID: 10.1016/j.atherosclerosis.2007.10.010] [PMID: 18061193]
Gregson J, Stirnadel-Farrant HA, Doobaree IU, Koro C. Variation of lipoprotein associated phospholipase A2 across demographic characteristics and cardiovascular risk factors: a systematic review of the literature. Atherosclerosis 2012; 225(1): 11-21.
[] [PMID: 22784637]
Yamada Y, Yoshida H, Ichihara S, Imaizumi T, Satoh K, Yokota M. Correlations between plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and PAF-AH genotype, age, and atherosclerosis in a Japanese population. Atherosclerosis 2000; 150(1): 209-16.
[] [PMID: 10781653]
Hiramoto M, Yoshida H, Imaizumi T, Yoshimizu N, Satoh K. A mutation in plasma platelet-activating factor acetylhydrolase (Val279-->Phe) is a genetic risk factor for stroke. Stroke 1997; 28(12): 2417-20.
[] [PMID: 9412624]
Ichihara S, Yamada Y, Yokota M. Association of a G994-->T missense mutation in the plasma platelet-activating factor acetylhydrolase gene with genetic susceptibility to nonfamilial dilated cardiomyopathy in Japanese. Circulation 1998; 98(18): 1881-5.
[] [PMID: 9799208]
Stafforini DM, Satoh K, Atkinson DL, et al. Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase. J Clin Invest 1996; 97(12): 2784-91.
[] [PMID: 8675689]
Jang Y, Waterworth D, Lee JE, et al. Carriage of the V279F null allele within the gene encoding Lp-PLA2 is protective from coronary artery disease in South Korean males. PLoS One 2011; 6(4)e18208
[] [PMID: 21490708]
Ninio E, Tregouet D, Carrier JL, et al. Platelet-activating factor-acetylhydrolase and PAF-receptor gene haplotypes in relation to future cardiovascular event in patients with coronary artery disease. Hum Mol Genet 2004; 13(13): 1341-51.
[] [PMID: 15115767]
Wootton PT, Stephens JW, Hurel SJ, et al. Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus. Atherosclerosis 2006; 189(1): 149-56.
[] [PMID: 16438975]
Liu PY, Li YH, Wu HL, et al. Platelet-activating factor-acetylhydrolase A379V (exon 11) gene polymorphism is an independent and functional risk factor for premature myocardial infarction. J Thromb Haemost 2006; 4(5): 1023-8.
[] [PMID: 16689754]
Santoso A, Maulana R, Alzahra F, Maghfirah I, Putrinarita AD, Heriansyah T. Associations between four types of single-nucleotide polymorphisms in PLA2G7 gene and clinical atherosclerosis: a meta-analysis. Am J Cardiovasc Dis 2017; 7(6): 122-33.
[PMID: 29348973]
Blackie JA, Bloomer JC, Brown MJ, et al. The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003; 13(6): 1067-70.
[] [PMID: 12643913]
Serruys PW, García-García HM, Buszman P, et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008; 118(11): 1172-82.
[] [PMID: 18765397]
Wihastuti TA, Heriansyah T, Hanifa H, et al. Darapladib inhibits atherosclerosis development in type 2 diabetes mellitus Sprague-Dawley rat model. Endocr Regul 2018; 52(2): 69-75.
[] [PMID: 29715185]
Ridker PM, MacFadyen JG, Wolfert RL, Koenig W. Relationship of lipoprotein-associated phospholipase A2 mass and activity with incident vascular events among primary prevention patients allocated to placebo or to statin therapy: an analysis from the JUPITER trial. Clin Chem 2012; 58(5): 877-86.
[] [PMID: 22419750]
Prasad M, Lennon R, Barsness GW, et al. Chronic inhibition of lipoprotein-associated phospholipase A2 does not improve coronary endothelial function: A prospective, randomized-controlled trial. Int J Cardiol 2018; 253: 7-13.
[] [PMID: 29306475]
Choi WG, Prasad M, Lennon R, et al. Long-term darapladib use does not affect coronary plaque composition assessed using multimodality intravascular imaging modalities: a randomized-controlled study. Coron Artery Dis 2018; 29(2): 104-13.
[] [PMID: 29135482]
Millwood IY, Bennett DA, Walters RG, et al. A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults. Int J Epidemiol 2016; 45(5): 1588-99.
[] [PMID: 27301456]
Rosenson RS, Fraser H, Goulder MA, Hislop C. Anti-inflammatory effects of varespladib methyl in diabetic patients with acute coronary syndrome. Cardiovasc Drugs Ther 2011; 25(6): 539-44.
[] [PMID: 21989792]
Holmes MV, Simon T, Exeter HJ, et al. Secretory phospholipase A(2)-IIA and cardiovascular disease: a mendelian randomization study. J Am Coll Cardiol 2013; 62(21): 1966-76.
[] [PMID: 23916927]
Talmud PJ, Holmes MV. Deciphering the Causal Role of sPLA2s and Lp-PLA2 in Coronary Heart Disease. Arterioscler Thromb Vasc Biol 2015; 35(11): 2281-9.
[] [PMID: 26338298]

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