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.
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.
Sato
Hiroyasu
H
Biomembrane Signaling Project, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Tokyo 113-8613, Japan.
Kato
Rina
R
Isogai
Yuki
Y
Saka
Go-ichi
G
Ohtsuki
Mitsuhiro
M
Taketomi
Yoshitaka
Y
Yamamoto
Kei
K
Tsutsumi
Kae
K
Yamada
Joe
J
Masuda
Seiko
S
Ishikawa
Yukio
Y
Ishii
Toshiharu
T
Kobayashi
Tetsuyuki
T
Ikeda
Kazutaka
K
Taguchi
Ryo
R
Hatakeyama
Shinji
S
Hara
Shuntaro
S
Kudo
Ichiro
I
Itabe
Hiroyuki
H
Murakami
Makoto
M
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
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
Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1579-85
16601231
Stroke. 2006 Jul;37(7):1923-32
16741184
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14507-12
16973753
J Biol Chem. 2006 Nov 24;281(47):36420-33
17008322
FASEB J. 2006 Dec;20(14):2547-9
17077289
Dis Colon Rectum. 2007 Feb;50(2):223-31
17164967
Arterioscler Thromb Vasc Biol. 2007 Mar;27(3):600-6
17204667
J Exp Med. 2007 Apr 16;204(4):865-77
17403936
Hum Mol Genet. 2007 Jun 15;16(12):1437-44
17545304
Immunol Rev. 2007 Oct;219:187-203
17850490
J Immunol. 2007 Oct 1;179(7):4800-7
17878379
Biochim Biophys Acta. 2007 Nov;1771(11):1389-96
17980167
Biochem J. 2008 Jan 15;409(2):429-38
17868035
Atherosclerosis. 2008 Jan;196(1):81-91
17353016
Diabetes. 2006 Apr;55(4):935-41
16567514
Circ Res. 2000 Mar 31;86(6):707-14
10747008
J Biol Chem. 2000 Dec 22;275(51):39973-80
10988294
J Biol Chem. 2001 Mar 30;276(13):10083-96
11106649
Adv Immunol. 2001;77:163-94
11293116
Circ Res. 2001 Aug 17;89(4):298-304
11509445
Arthritis Rheum. 2001 Dec;44(12):2761-7
11762936
J Biol Chem. 2002 Feb 22;277(8):5849-57
11694541
J Biol Chem. 2002 May 24;277(21):19145-55
11877435
Circ Res. 2002 Jul 26;91(2):120-6
12142344
J Biol Chem. 2002 Aug 9;277(32):29116-24
12021277
Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E994-E1001
12376327
Prostaglandins Other Lipid Mediat. 2002 Aug;68-69:3-58
12432908
Br J Cancer. 2008 Feb 12;98(3):587-95
18212756
Circulation. 2008 Jun 10;117(23):2977-85
18506007
J Biol Chem. 2008 Aug 1;283(31):21640-8
18511424
J Biol Chem. 2000 Mar 17;275(11):7492-6
10713052
J Biol Chem. 1999 Nov 26;274(48):34203-11
10567392
Can J Biochem Physiol. 1959 Aug;37(8):911-7
13671378
Rapid Commun Mass Spectrom. 2004;18(24):3123-30
15565732
Biochem Biophys Res Commun. 2005 Jan 28;326(4):744-51
15607732
J Biol Chem. 2005 Jul 1;280(26):24987-98
15863501
J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Aug 25;823(1):26-36
15990370
J Biol Chem. 2005 Aug 19;280(33):29946-55
15970590
Biochim Biophys Acta. 2005 Sep 5;1736(1):38-50
16122976
J Biol Chem. 2005 Sep 23;280(38):32746-52
16040605
J Biol Chem. 2006 Mar 10;281(10):6691-8
16407308
Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):263-8
12588769
J Biol Chem. 2003 Mar 21;278(12):10657-67
12522102
J Biol Chem. 2003 May 16;278(20):18162-9
12642576
Circulation. 2003 Aug 12;108(6):741-7
12885756
Biochim Biophys Acta. 2003 Oct 21;1642(3):129-38
14572896
J Mol Cell Cardiol. 2003 Nov;35(11):1375-84
14596794
J Exp Med. 2004 Mar 15;199(6):763-74
15007093
Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):762-7
14962950
J Biol Chem. 2004 Apr 16;279(16):16488-94
14761945
J Clin Invest. 2004 Sep;114(6):784-94
15372102
Adv Lipid Res. 1968;6:1-68
4179999
J Lipid Res. 1978 May;19(4):514-8
96199
Annu Rev Biochem. 1983;52:223-61
6311077
Methods Enzymol. 1986;128:417-31
3724517
J Clin Invest. 1988 Mar;81(3):720-9
3125226
Gene. 1991 Dec 15;108(2):193-9
1660837
Am J Pathol. 1992 Mar;140(3):665-73
1372160
J Clin Invest. 1992 Sep;90(3):1138-44
1381720
Nature. 1993 Apr 29;362(6423):801-9
8479518
J Clin Invest. 1994 Feb;93(2):615-32
8113399
J Biol Chem. 1994 May 27;269(21):15274-9
8195164
Cell. 1995 Jun 16;81(6):957-66
7781071
J Clin Invest. 1996 Jan 1;97(1):250-7
8550843
J Clin Invest. 1996 May 15;97(10):2233-41
8636402
J Biol Chem. 1996 Oct 18;271(42):26307-14
8824283
Eur J Pharmacol. 1996 Jul 18;308(2):195-203
8840132
Gene. 1996 Nov 28;181(1-2):207-12
8973332
Biochem Biophys Res Commun. 1997 Aug 18;237(2):318-24
9268708
Nature. 1997 Dec 11;390(6660):618-22
9403692
Arterioscler Thromb Vasc Biol. 1998 Apr;18(4):519-25
9555856
J Biol Chem. 1998 Jun 5;273(23):14411-23
9603953
Biochemistry. 1998 Jun 23;37(25):9203-10
9636068
Biochim Biophys Acta. 1998 Oct 2;1394(1):57-64
9767110
Arterioscler Thromb Vasc Biol. 1999 May;19(5):1284-90
10323781
J Clin Invest. 1999 Jun;103(11):1597-604
10359569
Biochim Biophys Acta. 1999 Jul 9;1439(1):1-16
10395961
Circulation. 1999 Sep 21;100(12):1280-4
10491371