Lipoprotein-associated phospholipase A2 explained

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) also known as platelet-activating factor acetylhydrolase (PAF-AH) is a phospholipase A₂ enzyme that in humans is encoded by the PLA2G7 gene.^{[1] [2]} Lp-PLA₂ is a 45-kDa protein of 441 amino acids.^[3] It is one of several PAF acetylhydrolases.

Function

In the blood Lp-PLA₂ travels mainly with low-density lipoprotein (LDL). Less than 20% is associated with high-density lipoprotein HDL. Several lines of evidence suggest that HDL-associated Lp-PLA2 may substantially contribute to the HDL antiatherogenic activities.^[4] It is an enzyme produced by inflammatory cells and hydrolyzes oxidized phospholipids in LDL.

Lp-PLA₂ is platelet-activating factor (PAF) acetylhydrolase (EC 3.1.1.47), a secreted enzyme that catalyzes the degradation of PAF to inactive products by hydrolysis of the acetyl group at the sn-2 position, producing the biologically inactive products LYSO-PAF and acetate.^[5]

Clinical significance

Lp-PLA₂ is involved in the development of atherosclerosis,^[3] an observation that has prompted interest as a possible therapeutic target (see, e.g. the investigational drug Darapladib). In human atherosclerotic lesions, 2 main sources of Lp-PLA₂ can be identified, including that which is brought into the intima bound to LDL (from the circulation), and that which is synthesized de novo by plaque inflammatory cells (macrophages, T cells, mast cells)."

It is used as a marker for cardiac disease.^[6]

A meta-analysis involving a total of 79,036 participants in 32 prospective studies found that Lp-PLA₂ levels are positively correlated with increased risk of developing coronary heart disease and stroke.^[7]

See also

• Darapladib

Further reading

• Schröder HC, Perovic S, Kavsan V, Ushijima H, Müller WE . Mechanisms of prionSc- and HIV-1 gp120 induced neuronal cell death . Neurotoxicology . 19 . 4–5 . 683–8 . 1998 . 9745929 .
• Feng Y, Walsh CA . Protein-protein interactions, cytoskeletal regulation and neuronal migration . Nature Reviews. Neuroscience . 2 . 6 . 408–16 . June 2001 . 11389474 . 10.1038/35077559 . 14717115 .
• Tjoelker LW, Eberhardt C, Unger J, Trong HL, Zimmerman GA, McIntyre TM, Stafforini DM, Prescott SM, Gray PW . 6 . Plasma platelet-activating factor acetylhydrolase is a secreted phospholipase A2 with a catalytic triad . The Journal of Biological Chemistry . 270 . 43 . 25481–7 . October 1995 . 7592717 . 10.1074/jbc.270.43.25481 . free .
• Stafforini DM, Satoh K, Atkinson DL, Tjoelker LW, Eberhardt C, Yoshida H, Imaizumi T, Takamatsu S, Zimmerman GA, McIntyre TM, Gray PW, Prescott SM . 6 . Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase . The Journal of Clinical Investigation . 97 . 12 . 2784–91 . June 1996 . 8675689 . 507371 . 10.1172/JCI118733 .
• Yamada Y, Yokota M . Loss of activity of plasma platelet-activating factor acetylhydrolase due to a novel Gln281-->Arg mutation . Biochemical and Biophysical Research Communications . 236 . 3 . 772–5 . July 1997 . 9245731 . 10.1006/bbrc.1997.7047 .
• Mavoungou E, Georges-Courbot MC, Poaty-Mavoungou V, Nguyen HT, Yaba P, Delicat A, Georges AJ, Russo-Marie F . 6 . HIV and SIV envelope glycoproteins induce phospholipase A2 activation in human and macaque lymphocytes . Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology . 16 . 1 . 1–9 . September 1997 . 9377118 . 10.1097/00042560-199709010-00001 . free .
• Sapir T, Elbaum M, Reiner O . Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit . The EMBO Journal . 16 . 23 . 6977–84 . December 1997 . 9384577 . 1170301 . 10.1093/emboj/16.23.6977 .
• 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 . 28 . 12 . 2417–20 . December 1997 . 9412624 . 10.1161/01.str.28.12.2417 .
• Yamada Y, Ichihara S, Fujimura T, Yokota M . Identification of the G994--> T missense in exon 9 of the plasma platelet-activating factor acetylhydrolase gene as an independent risk factor for coronary artery disease in Japanese men . Metabolism . 47 . 2 . 177–81 . February 1998 . 9472966 . 10.1016/S0026-0495(98)90216-5 .
• Yoshida H, Imaizumi T, Fujimoto K, Itaya H, Hiramoto M, Yoshimizu N, Fukushi K, Satoh K . 6 . A mutation in plasma platelet-activating factor acetylhydrolase (Val279Phe) is a genetic risk factor for cerebral hemorrhage but not for hypertension . Thrombosis and Haemostasis . 80 . 3 . 372–5 . September 1998 . 9759612 . 10.1055/s-0037-1615214. 23924021 .
• Lecointe N, Meerabux J, Ebihara M, Hill A, Young BD . Molecular analysis of an unstable genomic region at chromosome band 11q23 reveals a disruption of the gene encoding the alpha2 subunit of platelet-activating factor acetylhydrolase (Pafah1a2) in human lymphoma . Oncogene . 18 . 18 . 2852–9 . May 1999 . 10362256 . 10.1038/sj.onc.1202645 . free .
• Kruse S, Mao XQ, Heinzmann A, Blattmann S, Roberts MH, Braun S, Gao PS, Forster J, Kuehr J, Hopkin JM, Shirakawa T, Deichmann KA . 6 . The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma . American Journal of Human Genetics . 66 . 5 . 1522–30 . May 2000 . 10733466 . 1378003 . 10.1086/302901 .
• Howard KM, Olson MS . The expression and localization of plasma platelet-activating factor acetylhydrolase in endotoxemic rats . The Journal of Biological Chemistry . 275 . 26 . 19891–6 . June 2000 . 10748027 . 10.1074/jbc.M001462200 . free .
• Min JH, Wilder C, Aoki J, Arai H, Inoue K, Paul L, Gelb MH . Platelet-activating factor acetylhydrolases: broad substrate specificity and lipoprotein binding does not modulate the catalytic properties of the plasma enzyme . Biochemistry . 40 . 15 . 4539–49 . April 2001 . 11294621 . 10.1021/bi002600g . 10.1.1.549.9621 .
• Quarck R, De Geest B, Stengel D, Mertens A, Lox M, Theilmeier G, Michiels C, Raes M, Bult H, Collen D, Van Veldhoven P, Ninio E, Holvoet P . 6 . Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice . Circulation . 103 . 20 . 2495–500 . May 2001 . 11369691 . 10.1161/01.cir.103.20.2495 . free .
• Unno N, Nakamura T, Mitsuoka H, Uchiyama T, Yamamoto N, Saito T, Sugatani J, Miwa M, Nakamura S . 6 . Association of a G994 -->T missense mutation in the plasma platelet-activating factor acetylhydrolase gene with risk of abdominal aortic aneurysm in Japanese . Annals of Surgery . 235 . 2 . 297–302 . February 2002 . 11807372 . 1422429 . 10.1097/00000658-200202000-00020 .

Notes and References

1. Tjoelker LW, Wilder C, Eberhardt C, Stafforini DM, Dietsch G, Schimpf B, Hooper S, Le Trong H, Cousens LS, Zimmerman GA, Yamada Y, McIntyre TM, Prescott SM, Gray PW . 6 . Anti-inflammatory properties of a platelet-activating factor acetylhydrolase . Nature . 374 . 6522 . 549–53 . April 1995 . 7700381 . 10.1038/374549a0 . 1995Natur.374..549T . 4338858 .
2. Tew DG, Southan C, Rice SQ, Lawrence MP, Li H, Boyd HF, Moores K, Gloger IS, Macphee CH . 6 . Purification, properties, sequencing, and cloning of a lipoprotein-associated, serine-dependent phospholipase involved in the oxidative modification of low-density lipoproteins . Arteriosclerosis, Thrombosis, and Vascular Biology . 16 . 4 . 591–9 . April 1996 . 8624782 . 10.1161/01.ATV.16.4.591 .
3. Zalewski A, Macphee C . Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target . Arteriosclerosis, Thrombosis, and Vascular Biology . 25 . 5 . 923–31 . May 2005 . 15731492 . 10.1161/01.ATV.0000160551.21962.a7 . 5778538 . free .
4. Tellis CC, Tselepis AD . The role of lipoprotein-associated phospholipase A2 in atherosclerosis may depend on its lipoprotein carrier in plasma . Biochimica et Biophysica Acta . 1791 . 5 . 327–38 . May 2009 . 19272461 . 10.1016/j.bbalip.2009.02.015 .
5. Web site: Entrez Gene: PLA2G7 phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma).
6. Mohler ER, Ballantyne CM, Davidson MH, Hanefeld M, Ruilope LM, Johnson JL, Zalewski A . 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 . Journal of the American College of Cardiology . 51 . 17 . 1632–41 . April 2008 . 18436114 . 10.1016/j.jacc.2007.11.079 .
7. Thompson A, Gao P, Orfei L, Watson S, Di Angelantonio E, Kaptoge S, Ballantyne C, Cannon CP, Criqui M, Cushman M, Hofman A, Packard C, Thompson SG, Collins R, Danesh J . 6 . Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies . Lancet . 375 . 9725 . 1536–44 . May 2010 . 20435228 . 2864403 . 10.1016/S0140-6736(10)60319-4.
   • News: 29 April 2010 . Blood protein increases heart disease risk . BBC News .