title: Analyses of group III secreted phospholipase A2 transgenic mice reveal potential participation of this enzyme in plasma lipoprotein modification, macrophage foam cell formation, and atherosclerosis.
abstract: Among the many mammalian secreted phospholipase A2 (sPLA2) enzymes, PLA2G3 (group III secreted phospholipase A2) is unique in that it possesses unusual N- and C-terminal domains and in that its central sPLA2 domain is homologous to bee venom PLA2 rather than to other mammalian sPLA2s. To elucidate the in vivo actions of this atypical sPLA2, we generated transgenic (Tg) mice overexpressing human PLA2G3. Despite marked increases in PLA2 activity and mature 18-kDa PLA2G3 protein in the circulation and tissues, PLA2G3 Tg mice displayed no apparent abnormality up to 9 months of age. However, alterations in plasma lipoproteins were observed in PLA2G3 Tg mice compared with control mice. In vitro incubation of low density (LDL) and high density (HDL) lipoproteins with several sPLA2s showed that phosphatidylcholine was efficiently converted to lysophosphatidylcholine by PLA2G3 as well as by PLA2G5 and PLA2G10, to a lesser extent by PLA2G2F, and only minimally by PLA2G2A and PLA2G2E. PLA2G3-modified LDL, like PLA2G5- or PLA2G10-treated LDL, facilitated the formation of foam cells from macrophages ex vivo. Accumulation of PLA2G3 was detected in the atherosclerotic lesions of humans and apoE-deficient mice. Furthermore, following an atherogenic diet, aortic atherosclerotic lesions were more severe in PLA2G3 Tg mice than in control mice on the apoE-null background, in combination with elevated plasma lysophosphatidylcholine and thromboxane A2 levels. These results collectively suggest a potential functional link between PLA2G3 and atherosclerosis, as has recently been proposed for PLA2G5 and PLA2G10.
authors.affiliation: Biomembrane Signaling Project, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Tokyo 113-8613, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Sato
authors.forename: Rina
authors.initials: R
authors.lastname: Kato
authors.forename: Yuki
authors.initials: Y
authors.lastname: Isogai
authors.forename: Go-ichi
authors.initials: G
authors.lastname: Saka
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ohtsuki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Taketomi
authors.forename: Kei
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Kae
authors.initials: K
authors.lastname: Tsutsumi
authors.forename: Joe
authors.initials: J
authors.lastname: Yamada
authors.forename: Seiko
authors.initials: S
authors.lastname: Masuda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ishii
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Hatakeyama
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Hara
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kudo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Itabe
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001514:Bee Venoms / Q000737:chemistry; D004036:Diet, Atherogenic; D005487:Foam Cells / Q000201:enzymology* / Q000473:pathology; D054520:Group III Phospholipases A2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010713:Phosphatidylcholines / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D001514:Bee Venoms; D007527:Isoenzymes; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D010713:Phosphatidylcholines; D054520:Group III Phospholipases A2; C484163:PLA2G3 protein, human
references.citation: Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1579-85
references.pmid: 16601231
references.citation: Stroke. 2006 Jul;37(7):1923-32
references.pmid: 16741184
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14507-12
references.pmid: 16973753
references.citation: J Biol Chem. 2006 Nov 24;281(47):36420-33
references.pmid: 17008322
references.citation: FASEB J. 2006 Dec;20(14):2547-9
references.pmid: 17077289
references.citation: Dis Colon Rectum. 2007 Feb;50(2):223-31
references.pmid: 17164967
references.citation: Arterioscler Thromb Vasc Biol. 2007 Mar;27(3):600-6
references.pmid: 17204667
references.citation: J Exp Med. 2007 Apr 16;204(4):865-77
references.pmid: 17403936
references.citation: Hum Mol Genet. 2007 Jun 15;16(12):1437-44
references.pmid: 17545304
references.citation: Immunol Rev. 2007 Oct;219:187-203
references.pmid: 17850490
references.citation: J Immunol. 2007 Oct 1;179(7):4800-7
references.pmid: 17878379
references.citation: Biochim Biophys Acta. 2007 Nov;1771(11):1389-96
references.pmid: 17980167
references.citation: Biochem J. 2008 Jan 15;409(2):429-38
references.pmid: 17868035
references.citation: Atherosclerosis. 2008 Jan;196(1):81-91
references.pmid: 17353016
references.citation: Diabetes. 2006 Apr;55(4):935-41
references.pmid: 16567514
references.citation: Circ Res. 2000 Mar 31;86(6):707-14
references.pmid: 10747008
references.citation: J Biol Chem. 2000 Dec 22;275(51):39973-80
references.pmid: 10988294
references.citation: J Biol Chem. 2001 Mar 30;276(13):10083-96
references.pmid: 11106649
references.citation: Adv Immunol. 2001;77:163-94
references.pmid: 11293116
references.citation: Circ Res. 2001 Aug 17;89(4):298-304
references.pmid: 11509445
references.citation: Arthritis Rheum. 2001 Dec;44(12):2761-7
references.pmid: 11762936
references.citation: J Biol Chem. 2002 Feb 22;277(8):5849-57
references.pmid: 11694541
references.citation: J Biol Chem. 2002 May 24;277(21):19145-55
references.pmid: 11877435
references.citation: Circ Res. 2002 Jul 26;91(2):120-6
references.pmid: 12142344
references.citation: J Biol Chem. 2002 Aug 9;277(32):29116-24
references.pmid: 12021277
references.citation: Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E994-E1001
references.pmid: 12376327
references.citation: Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:3-58
references.pmid: 12432908
references.citation: Br J Cancer. 2008 Feb 12;98(3):587-95
references.pmid: 18212756
references.citation: Circulation. 2008 Jun 10;117(23):2977-85
references.pmid: 18506007
references.citation: J Biol Chem. 2008 Aug 1;283(31):21640-8
references.pmid: 18511424
references.citation: J Biol Chem. 2000 Mar 17;275(11):7492-6
references.pmid: 10713052
references.citation: J Biol Chem. 1999 Nov 26;274(48):34203-11
references.pmid: 10567392
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: Rapid Commun Mass Spectrom. 2004;18(24):3123-30
references.pmid: 15565732
references.citation: Biochem Biophys Res Commun. 2005 Jan 28;326(4):744-51
references.pmid: 15607732
references.citation: J Biol Chem. 2005 Jul 1;280(26):24987-98
references.pmid: 15863501
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Aug 25;823(1):26-36
references.pmid: 15990370
references.citation: J Biol Chem. 2005 Aug 19;280(33):29946-55
references.pmid: 15970590
references.citation: Biochim Biophys Acta. 2005 Sep 5;1736(1):38-50
references.pmid: 16122976
references.citation: J Biol Chem. 2005 Sep 23;280(38):32746-52
references.pmid: 16040605
references.citation: J Biol Chem. 2006 Mar 10;281(10):6691-8
references.pmid: 16407308
references.citation: Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):263-8
references.pmid: 12588769
references.citation: J Biol Chem. 2003 Mar 21;278(12):10657-67
references.pmid: 12522102
references.citation: J Biol Chem. 2003 May 16;278(20):18162-9
references.pmid: 12642576
references.citation: Circulation. 2003 Aug 12;108(6):741-7
references.pmid: 12885756
references.citation: Biochim Biophys Acta. 2003 Oct 21;1642(3):129-38
references.pmid: 14572896
references.citation: J Mol Cell Cardiol. 2003 Nov;35(11):1375-84
references.pmid: 14596794
references.citation: J Exp Med. 2004 Mar 15;199(6):763-74
references.pmid: 15007093
references.citation: Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):762-7
references.pmid: 14962950
references.citation: J Biol Chem. 2004 Apr 16;279(16):16488-94
references.pmid: 14761945
references.citation: J Clin Invest. 2004 Sep;114(6):784-94
references.pmid: 15372102
references.citation: Adv Lipid Res. 1968;6:1-68
references.pmid: 4179999
references.citation: J Lipid Res. 1978 May;19(4):514-8
references.pmid: 96199
references.citation: Annu Rev Biochem. 1983;52:223-61
references.pmid: 6311077
references.citation: Methods Enzymol. 1986;128:417-31
references.pmid: 3724517
references.citation: J Clin Invest. 1988 Mar;81(3):720-9
references.pmid: 3125226
references.citation: Gene. 1991 Dec 15;108(2):193-9
references.pmid: 1660837
references.citation: Am J Pathol. 1992 Mar;140(3):665-73
references.pmid: 1372160
references.citation: J Clin Invest. 1992 Sep;90(3):1138-44
references.pmid: 1381720
references.citation: Nature. 1993 Apr 29;362(6423):801-9
references.pmid: 8479518
references.citation: J Clin Invest. 1994 Feb;93(2):615-32
references.pmid: 8113399
references.citation: J Biol Chem. 1994 May 27;269(21):15274-9
references.pmid: 8195164
references.citation: Cell. 1995 Jun 16;81(6):957-66
references.pmid: 7781071
references.citation: J Clin Invest. 1996 Jan 1;97(1):250-7
references.pmid: 8550843
references.citation: J Clin Invest. 1996 May 15;97(10):2233-41
references.pmid: 8636402
references.citation: J Biol Chem. 1996 Oct 18;271(42):26307-14
references.pmid: 8824283
references.citation: Eur J Pharmacol. 1996 Jul 18;308(2):195-203
references.pmid: 8840132
references.citation: Gene. 1996 Nov 28;181(1-2):207-12
references.pmid: 8973332
references.citation: Biochem Biophys Res Commun. 1997 Aug 18;237(2):318-24
references.pmid: 9268708
references.citation: Nature. 1997 Dec 11;390(6660):618-22
references.pmid: 9403692
references.citation: Arterioscler Thromb Vasc Biol. 1998 Apr;18(4):519-25
references.pmid: 9555856
references.citation: J Biol Chem. 1998 Jun 5;273(23):14411-23
references.pmid: 9603953
references.citation: Biochemistry. 1998 Jun 23;37(25):9203-10
references.pmid: 9636068
references.citation: Biochim Biophys Acta. 1998 Oct 2;1394(1):57-64
references.pmid: 9767110
references.citation: Arterioscler Thromb Vasc Biol. 1999 May;19(5):1284-90
references.pmid: 10323781
references.citation: J Clin Invest. 1999 Jun;103(11):1597-604
references.pmid: 10359569
references.citation: Biochim Biophys Acta. 1999 Jul 9;1439(1):1-16
references.pmid: 10395961
references.citation: Circulation. 1999 Sep 21;100(12):1280-4
references.pmid: 10491371