Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress

Group IIA secretory phospholipase A2 (sPLA2) is an acute-phase protein mediating decreased plasma HDL cholesterol and increased atherosclerosis. This study investigated the impact of macrophage-specific sPLA2 overexpression on lipoprotein metabolism and atherogenesis. Macrophages from sPLA2 transgenic mice have 2.5 times increased rates of LDL oxidation (thiobarbituric acid-reactive substances formation) in vitro (59 ± 5 vs. 24 ± 4 nmol malondialdehyde/mg protein; P < 0.001) dependent on functional 12/15-lipoxygenase (12/15-LO). Low density lipoprotein receptor-deficient (LDLR−/−) mice were transplanted with bone marrow from either sPLA2 transgenic mice (sPLA2→ LDLR−/−; n = 19) or wild-type C57BL/6 littermates (C57 BL/6→LDLR−/−; n = 19) and maintained for 8 weeks on chow and then for 9 weeks on a Western-type diet. Plasma sPLA2 activity and plasma lipoprotein profiles were not significantly different between sPLA2→LDLR−/− and C57BL/6→LDLR−/− mice. Aortic root atherosclerosis was increased by 57% in sPLA2→LDLR−/− mice compared with C57BL/6→LDLR−/− controls (P < 0.05). Foam cell formation in vitro and in vivo was increased significantly. Urinary, plasma, and aortic levels of the isoprostane 8,12-iso-iPF2α-VI and aortic levels of 12/15-LO reaction products were each significantly higher (P < 0.001) in sPLA2→LDLR−/− compared with C57BL/6→LDLR−/− mice, indicating significantly increased in vivo oxidative stress in sPLA2→ LDLR−/−.These data demonstrate that macrophage-specific overexpression of human sPLA2 increases atherogenesis by directly modulating foam cell formation and in vivo oxidative stress without any effect on systemic sPLA2 activity and lipoprotein metabolism. Group IIA secretory phospholipase A2 (sPLA2) is an acute-phase protein mediating decreased plasma HDL cholesterol and increased atherosclerosis. This study investigated the impact of macrophage-specific sPLA2 overexpression on lipoprotein metabolism and atherogenesis. Macrophages from sPLA2 transgenic mice have 2.5 times increased rates of LDL oxidation (thiobarbituric acid-reactive substances formation) in vitro (59 ± 5 vs. 24 ± 4 nmol malondialdehyde/mg protein; P < 0.001) dependent on functional 12/15-lipoxygenase (12/15-LO). Low density lipoprotein receptor-deficient (LDLR−/−) mice were transplanted with bone marrow from either sPLA2 transgenic mice (sPLA2→ LDLR−/−; n = 19) or wild-type C57BL/6 littermates (C57 BL/6→LDLR−/−; n = 19) and maintained for 8 weeks on chow and then for 9 weeks on a Western-type diet. Plasma sPLA2 activity and plasma lipoprotein profiles were not significantly different between sPLA2→LDLR−/− and C57BL/6→LDLR−/− mice. Aortic root atherosclerosis was increased by 57% in sPLA2→LDLR−/− mice compared with C57BL/6→LDLR−/− controls (P < 0.05). Foam cell formation in vitro and in vivo was increased significantly. Urinary, plasma, and aortic levels of the isoprostane 8,12-iso-iPF2α-VI and aortic levels of 12/15-LO reaction products were each significantly higher (P < 0.001) in sPLA2→LDLR−/− compared with C57BL/6→LDLR−/− mice, indicating significantly increased in vivo oxidative stress in sPLA2→ LDLR−/−. These data demonstrate that macrophage-specific overexpression of human sPLA2 increases atherogenesis by directly modulating foam cell formation and in vivo oxidative stress without any effect on systemic sPLA2 activity and lipoprotein metabolism. Atherosclerosis is increasingly considered to have an inflammatory component (1Ross R. Atherosclerosis—an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126Google Scholar). While the atherosclerotic plaque displays the features of a localized inflammation within the vascular wall (2Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.Nat. Med. 2002; 8: 1211-1217Google Scholar, 3Lee R.T. Libby P. The unstable atheroma.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1859-1867Google Scholar), markers of systemic inflammation such as C-reactive protein have been found to be predictive of future cardiovascular events (4Ridker P.M. Buring J.E. Shih J. Matias M. Hennekens C.H. Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women.Circulation. 1998; 98: 731-733Google Scholar, 5Ridker P.M. Hennekens C.H. Roitman-Johnson B. Stampfer M.J. Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men.Lancet. 1998; 351: 88-92Google Scholar, 6Rader D.J. Inflammatory markers of coronary risk.N. Engl. J. Med. 2000; 343: 1179-1182Google Scholar). The type IIA secretory phospholipase A2 (sPLA2) is an acute-phase protein expressed in response to a variety of proinflammatory cytokines by a number of different tissues and cell types, mainly of mesenchymal origin (7Tischfield J.A. A reassessment of the low molecular weight phospholipase A2 gene family in mammals.J. Biol. Chem. 1997; 272: 17247-17250Google Scholar, 8Kudo I. Murakami M. Phospholipase A2 enzymes.Prostaglandins Other Lipid Mediat. 2002; 68–69: 3-58Google Scholar, 9Hurt-Camejo E. Camejo G. Peilot H. Oorni K. Kovanen P. Phospholipase A2 in vascular disease.Circ. Res. 2001; 89: 298-304Google Scholar, 10Nevalainen T.J. Haapamaki M.M. Gronroos J.N. Roles of secretory phospholipases A2 in inflammatory diseases and trauma.Biochim. Biophys. Acta. 2000; 1488: 83-90Google Scholar, 11Balsinde J. Balboa M.A. Insel P.A. Dennis E.A. Regulation and inhibition of phospholipase A2.Annu. Rev. Pharmacol. Toxicol. 1999; 39: 175-189Google Scholar, 12Peilot H. Rosengren B. Bondjers G. Hurt-Camejo E. Interferon-gamma induces secretory group IIA phospholipase A2 in human arterial smooth muscle cells. Involvement of cell differentiation, STAT-3 activation, and modulation by other cytokines.J. Biol. Chem. 2000; 275: 22895-22904Google Scholar). Increased sPLA2 plasma levels have been reported in patients with various acute and chronic inflammatory conditions (8Kudo I. Murakami M. Phospholipase A2 enzymes.Prostaglandins Other Lipid Mediat. 2002; 68–69: 3-58Google Scholar, 10Nevalainen T.J. Haapamaki M.M. Gronroos J.N. Roles of secretory phospholipases A2 in inflammatory diseases and trauma.Biochim. Biophys. Acta. 2000; 1488: 83-90Google Scholar). Notably, patients with atherosclerotic cardiovascular disease have significantly higher circulating sPLA2 levels compared with controls (13Kugiyama K. Ota Y. Takazoe K. Moriyama Y. Kawano H. Miyao Y. Sakamoto T. Soejima H. Ogawa H. Doi H. et al.Circulating levels of secretory type II phospholipase A2 predict coronary events in patients with coronary artery disease.Circulation. 1999; 100: 1280-1284Google Scholar, 14Kugiyama K. Ota Y. Sugiyama S. Kawano H. Doi H. Soejima H. Miyamoto S. Ogawa H. Takazoe K. Yasue H. Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina J. 2000; Scholar), and in sPLA2 levels were found to have a higher predictive value for future coronary events C-reactive protein (13Kugiyama K. Ota Y. Takazoe K. Moriyama Y. Kawano H. Miyao Y. Sakamoto T. Soejima H. Ogawa H. Doi H. et al.Circulating levels of secretory type II phospholipase A2 predict coronary events in patients with coronary artery disease.Circulation. 1999; 100: 1280-1284Google Scholar). in that sPLA2 a in the of atherogenesis and that as as systemic be mice human sPLA2 T.J. of human group II in transgenic mice in in the of inflammatory have decreased HDL cholesterol plasma levels to increased of as as HDL D. D.J. of secretory phospholipase A2 and of density lipoprotein and Biol. Chem. 2000; 275: Scholar, P.M. J. HDL by secretory phospholipase A2 type and HDL Lipid Res. 2000; Scholar, D. D.J. secretory phospholipase A2 (sPLA2) decreased plasma levels of and in response to inflammation of A in human transgenic Thromb. Vasc. Biol. 2002; Scholar). These mice increased atherosclerosis an for weeks on a chow B. M. M. et of group II secretory phospholipase A2 in atherosclerosis. Increased atherogenesis and in transgenic mice group phospholipase Thromb. Vasc. 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Biol. 1998; Scholar). that of human sPLA2 in atherogenesis bone marrow from sPLA2 transgenic mice low density lipoprotein receptor-deficient (LDLR−/−) demonstrate that a Western-type for 9 weeks significantly increased atherosclerosis in the group transplanted with the sPLA2 transgenic bone These data with the of a study that was was in M.A. group IIA secretory phospholipase A2 increases atherosclerotic formation in LDL receptor-deficient Thromb. Vasc. Biol. Scholar). for the increased atherogenesis by by increased 12/15-lipoxygenase of oxidative as by LDL oxidation by sPLA2 transgenic in vitro and increased isoprostane formation in and by increased foam cell formation by in vitro and in The human group IIA sPLA2 transgenic mice in study have been T.J. of human group II in transgenic mice in in the of inflammatory Scholar, D. D.J. of secretory phospholipase A2 and of density lipoprotein and Biol. Chem. 2000; 275: Scholar). mice, of the is by the human group IIA sPLA2 for of the by inflammatory sPLA2 D.J. inflammation increases of HDL of mice human J. Scholar). The sPLA2 transgenic been to the C57BL/6 for The were in with to and chow diet. mice were from The as and the The were in and to and were maintained on without cholesterol or were a Western-type and cholesterol The was with and and were in with the were by the and the for of and with and without for were by with of 1 by and on a cell density of 4 in with 4 were times with to and various conditions as from sPLA2 transgenic mice and C57BL/6 controls were for 24 in with the of human type IIA was the with and the with to the human type IIA sPLA2 to the number was on of the The of the human type IIA sPLA2 protein in cell of the was by as D. D.J. secretory phospholipase A2 (sPLA2) decreased plasma levels of and in response to inflammation of A in human transgenic Thromb. Vasc. Biol. 2002; a The sPLA2 activity was on cell and plasma as D.J. A for in vivo of to and Med. Scholar). a of as a were by sPLA2 and human LDL was by < < and within The protein of the was the study oxidation of LDL M.J. oxidative of low density lipoprotein of to the low density lipoprotein Lipid Res. Scholar), were as and in LDL for the the of the the LDL were and for and was to the a concentration of to The of LDL oxidation was by acid-reactive substances formation in as as a M.J. oxidative of low density lipoprotein of to the low density lipoprotein Lipid Res. Scholar). controls were and the were from the protein was with the and to the as G. S. P. H. D.J. of and in disease by gene of 2001; Scholar). for LDL oxidation expressed in of of the of 12/15-LO in LDL the a concentration of is to was to from sPLA2 transgenic mice or wild-type C57BL/6 littermates 1 the of LDL in Biol. Chem. 2001; Scholar). formation was of of 12/15-LO of protein was by to and with a 12/15-LO a of as of and of Biol. Chem. Scholar). foam cell formation in LDL was by LDL with in for from sPLA2 transgenic mice or wild-type C57BL/6 littermates were for 24 with cholesterol and cholesterol were were by cholesterol from cholesterol was from from C57BL/6 mice and sPLA2 transgenic by the was from of levels were on an to the of A and were as and A levels were to the of the and and and bone marrow mice were to a of 9 4 an with a 1 marrow was by the and from sPLA2 transgenic mice or wild-type C57BL/6 littermates with were by the a bone marrow by the The of the mice was in from bone marrow by weeks in the and the of the human type IIA sPLA2 T.J. of human group II in transgenic mice in in the of inflammatory Scholar), a Notably, were each mice sPLA2 transgenic bone marrow as as mice C57BL/6 bone and the data the of of an of was from mice by The of and and in were The of cholesterol and the different lipoprotein in was by of of of each a as M. E. G. J. et controls to atherosclerosis and 2002; Scholar). cholesterol and in the were the of atherosclerosis the aortic transplanted mice were 9 weeks of the Western-type diet. The arterial was in with for a in the The aortic as as the and were and in The atherosclerotic in of the aortic root was the of a to a and was from the of the the of were with of G. The for the of The was the density was by the number of The of in the was to the of the of 12/15-LO in atherosclerotic were a for 12/15-LO of and of Biol. Chem. Scholar). Urinary, plasma, and aortic levels of the isoprostane 8,12-iso-iPF2α-VI were by as D. D.J. J. isoprostane in vivo and atherosclerosis in Med. 1998; Scholar). was for 24 from of from mice were for and plasma was and were with a of and by and by D. D.J. J. isoprostane in vivo and atherosclerosis in Med. 1998; Scholar, T. Y. J. D. of atherosclerosis in lipoprotein mice with vascular Scholar). from mice were and in and and was for 1 and the levels of 8,12-iso-iPF2α-VI were as and levels were by as D. Y. K. J.A. is increased in in oxidative J. Scholar). was the for the expressed as ± were and for was P < human sPLA2 is expressed by from sPLA2 transgenic mice. a was by protein not be by indicating of the not with that the human sPLA2 is by inflammatory in mice D. D.J. secretory phospholipase A2 (sPLA2) decreased plasma levels of and in response to inflammation of A in human transgenic Thromb. Vasc. Biol. 2002; Scholar, D.J. inflammation increases of HDL of mice human J. Scholar), a was for the sPLA2 by in from sPLA2 transgenic mice, human sPLA2 was in C57BL/6 mice sPLA2 protein in of sPLA2 transgenic mice of from sPLA2 transgenic mice significantly higher sPLA2 activity compared with C57BL/6 indicating the of functional sPLA2 protein in from sPLA2 transgenic mice ± vs. ± density P < 0.001) of functional secretory phospholipase A2 (sPLA2) by from human sPLA2 transgenic mice. of of human sPLA2 in from sPLA2 transgenic mice and C57BL/6 a and as a human sPLA2 for human sPLA2 and sPLA2 activity each on cell 24 of as in in as ± different from (P < of functional secretory phospholipase A2 (sPLA2) by from human sPLA2 transgenic mice. of of human sPLA2 in from sPLA2 transgenic mice and C57BL/6 a and as a human sPLA2 for human sPLA2 and sPLA2 activity each on cell 24 of as in in as ± different from (P < from sPLA2 transgenic and C57BL/6 mice were with LDL to LDL and 24 formation was in from the sPLA2 transgenic significantly higher formation ± 4 vs. ± nmol malondialdehyde/mg cell P < 0.001) 24 (59 ± 5 vs. 24 ± 4 nmol malondialdehyde/mg cell P < 0.001) of C57BL/6 12/15-LO is for LDL oxidation and between 12/15-LO and sPLA2 been reported S. D. of low density lipoprotein by phospholipase A2 oxidative Lipid Res. Scholar, J. R. phospholipase A2 and lipoprotein and in 1998; Scholar), as a the of 12/15-LO in by from sPLA2 transgenic mice increased 12/15-LO protein levels compared with wild-type controls a 12/15-LO LDL oxidation was significantly in the (P < in sPLA2 transgenic LDL oxidation was by the of the (P < and to that were not significantly different from the levels of LDL oxidation in either with or without the is in LDL oxidation by from sPLA2 transgenic mice. for LDL oxidation by from sPLA2 transgenic mice and wild-type littermates in the or of of the 12/15-LO data as ± with the value in without to different from (P < 0.05). different from the in the without the of (P < 0.05). acid-reactive foam cell formation in from sPLA2 transgenic mice and wild-type controls were with for 24 a significantly higher compared with controls ± vs. ± cell P < indicating increased foam cell formation of the on the oxidation of levels of A as by were not significantly different between of mice ± in sPLA2 transgenic vs. ± in the of sPLA2 in lipoprotein metabolism and atherosclerotic were that sPLA2 in by of bone marrow from sPLA2 transgenic mice and C57BL/6 littermates to mice, an for atherosclerosis. mice were maintained for 8 weeks on then were a Western-type for an 9 the of the plasma sPLA2 activity was not significantly different between mice that sPLA2 transgenic bone marrow and transplanted with bone marrow ± vs. ± Plasma levels of and not significantly between sPLA2 transgenic and bone marrow transplanted mice any of the study the cholesterol in the different lipoprotein was not different between of mice of the Western-type the of the sPLA2 activity the mainly of the HDL D. D.J. of secretory phospholipase A2 and of density lipoprotein and Biol. Chem. 2000; 275: Scholar, D. D.J. secretory phospholipase A2 (sPLA2) decreased plasma levels of and in response to inflammation of A in human transgenic Thromb. Vasc. Biol. 2002; Scholar, D.J. inflammation increases of HDL of mice human J. Scholar), the of the of the was in of mice 9 weeks on the Western-type not within the HDL of the mice that bone marrow from sPLA2 transgenic mice compared with controls profiles in mice and with either human sPLA2 transgenic bone marrow or wild-type C57BL/6 bone cholesterol ± ± ± ± ± ± cholesterol ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± bone marrow low density lipoprotein secretory phospholipase ± weeks 8 weeks the Western-type and weeks the of the 9 weeks of the Western-type diet. in a cholesterol and profiles in mice transplanted with either sPLA2 transgenic or C57BL/6 bone plasma were to a and cholesterol and were in each with cholesterol profiles and 9 weeks a Western-type as as profiles and 9 weeks a Western-type diet. as ± n = cholesterol and profiles in mice transplanted with either sPLA2 transgenic or C57BL/6 bone plasma were to a and cholesterol and were in each with cholesterol profiles and 9 weeks a Western-type as as profiles and 9 weeks a Western-type diet. as ± n = cholesterol and profiles in mice transplanted with either sPLA2 transgenic or C57BL/6 bone plasma were to a and cholesterol and were in each with cholesterol profiles and 9 weeks a Western-type as as profiles and 9 weeks a Western-type diet. as ± n = bone marrow low density lipoprotein secretory phospholipase ± weeks 8 weeks the Western-type and weeks the of the 9 weeks of the Western-type diet. 9 weeks on the Western-type mice were and the of atherosclerosis in the aortic root was mice that were transplanted with sPLA2 transgenic bone marrow significantly atherosclerotic mice transplanted with C57BL/6 bone marrow ± vs. ± P < atherosclerosis in mice transplanted with either sPLA2 transgenic or C57BL/6 bone marrow 9 weeks of a Western-type diet. of aortic root atherosclerosis as in as ± different from (P < 0.05). n = of atherosclerotic formation in a transplanted with C57BL/6 bone marrow and in a transplanted with sPLA2 transgenic bone marrow atherosclerosis in mice transplanted with either sPLA2 transgenic or C57BL/6 bone marrow 9 weeks of a Western-type diet. of aortic root atherosclerosis as in as ± different from (P < 0.05). n = of atherosclerotic formation in a transplanted with C57BL/6 bone marrow and in a transplanted with sPLA2 transgenic bone marrow The of the atherosclerotic was low in of mice, a higher levels was in mice transplanted with bone marrow from sPLA2 transgenic mice compared with controls ± vs. ± P = the atherosclerotic were in of the mice transplanted with sPLA2 transgenic bone marrow and in 5 of the transplanted mice. on were in mice transplanted with either human sPLA2 transgenic or wild-type C57BL/6 bone ± ± ± ± ± ± different from the group (P < number ± ± different from the group (P < of of ± ± ± different from the group (P < 0.05). in a ± the was not significantly different between mice that sPLA2 transgenic bone marrow ± and with bone marrow ± the was significantly in mice transplanted with the sPLA2 transgenic bone marrow in controls ± vs. ± P = The number of was as a of in the number of was indicating that is not by sPLA2 overexpression in an the number of within the of mice that the sPLA2 transgenic bone marrow was significantly decreased compared with controls ± vs. ± P = indicating an increased of the foam cells. These an increased cholesterol within the foam in with the in vitro sPLA2 by significantly increased LDL oxidation in increased oxidative stress by sPLA2 a to the increased atherogenesis in mice that bone marrow from sPLA2 transgenic mice. a and of in vivo oxidative the of a 8,12-iso-iPF2α-VI T. Y. J. D. of atherosclerosis in lipoprotein mice with vascular Scholar). with mice bone transplanted with sPLA2 transgenic bone marrow significantly increased levels of 8,12-iso-iPF2α-VI in plasma ± vs. ± P < 0.001) as in ± vs. ± P < as a of oxidative aortic 8,12-iso-iPF2α-VI were increased significantly in the of mice that the sPLA2 transgenic bone marrow compared with controls ± vs. ± P < 0.001) of the isoprostane 8,12-iso-iPF2α-VI as a of in vivo oxidative the of the 9 weeks of Western-type to mice transplanted with either sPLA2 transgenic or C57BL/6 bone marrow 8,12-iso-iPF2α-VI were as in for plasma and as ± different from n = of the isoprostane 8,12-iso-iPF2α-VI as a of in vivo oxidative the of the 9 weeks of Western-type to mice transplanted with either sPLA2 transgenic or C57BL/6 bone marrow 8,12-iso-iPF2α-VI were as in for plasma and as ± different from n = the aortic of 12/15-LO in the of mice that the sPLA2 transgenic bone levels of ± vs. ± P = 0.001) ± vs. ± P < were significantly higher in of mice transplanted with the wild-type bone to in vitro demonstrate increased formation of 12/15-LO reaction products within the vascular wall of mice with the sPLA2 transgenic bone an increased activity of 12/15-LO in in The of study demonstrate that macrophage-specific overexpression of human sPLA2 atherogenesis in mice by foam cell formation as as vascular oxidative stress without plasma cholesterol levels and plasma sPLA2 for sPLA2 atherogenesis have been sPLA2 plasma HDL cholesterol mice human sPLA2 by the of have significantly decreased plasma HDL cholesterol levels D. D.J. of secretory phospholipase A2 and of density lipoprotein and Biol. Chem. 2000; 275: Scholar, D.J. inflammation increases of HDL of mice human J. Scholar, phospholipase on lipoprotein Lipid Res. 1997; Scholar). Plasma sPLA2 activity M.A. E. Phospholipase A2 from plasma of patients with is with and for functional J. as as protein D. D.J. secretory phospholipase A2 (sPLA2) decreased plasma levels of and in response to inflammation of A in human transgenic Thromb. Vasc. Biol. 2002; found mainly with the HDL in plasma cholesterol the different lipoprotein was not significantly different between mice transplanted with sPLA2 transgenic bone marrow and These data demonstrate that macrophage-specific sPLA2 within the vascular wall is not to systemic HDL levels and lipoprotein metabolism. sPLA2 induces the formation of LDL K. M. Kovanen induces and phospholipase A2 of low density lipoprotein to increased of LDL to human aortic Biol. Chem. 1998; Scholar, Oorni K. Hurt-Camejo E. Kovanen of LDL by human secretory phospholipase A2 induces and of LDL to human aortic Thromb. Vasc. Biol. 2001; Scholar, Oorni K. M. Kovanen of LDL by phospholipase A2 induces in the and in the of Thromb. Vasc. Biol. 1999; Scholar). LDL is a of atherosclerotic K. M. Kovanen and formation of low density lipoprotein molecular and on Lipid Res. 2000; Scholar). This type of LDL increases the of LDL for and the formation of foam and within the vascular wall K. M. Kovanen and formation of low density lipoprotein molecular and on Lipid Res. 2000; Scholar, of by 2002; Scholar). This have to the in foam cell formation that in the of foam cell within the plaque was not different between the foam cell was increased in vivo in mice transplanted with sPLA2 transgenic bone the number of of was decreased in indicating an increased of the foam cells. sPLA2 transgenic increased of and in HDL LDL vitro cell and vascular smooth muscle cell that HDL not LDL oxidation B. J. M. et of group II secretory phospholipase A2 in atherosclerosis. of Thromb. Vasc. Biol. 1999; Scholar). This been to a of activity from HDL B. J. M. et of group II secretory phospholipase A2 in atherosclerosis. of Thromb. Vasc. Biol. 1999; Scholar). is a to B. The gene family and coronary 2002; Scholar). from sPLA2 transgenic mice maintained on an with for weeks increased levels of B. J. M. et of group II secretory phospholipase A2 in atherosclerosis. of Thromb. Vasc. Biol. 1999; Scholar). macrophage-specific overexpression of sPLA2 in transgenic mice not HDL activity M.J. M. I. B. overexpression of group sPLA2 increases atherosclerosis and Lipid Res. Scholar). in vitro data demonstrate that sPLA2 by significantly LDL in the of HDL a for sPLA2 in LDL data the in vivo that sPLA2 induces increased oxidative an to atherogenesis (2Steinberg D. Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime.Nat. Med. 2002; 8: 1211-1217Google Scholar, stress and cardiovascular and human Scholar, to and in J. Scholar, the 2001; Scholar). oxidative to the formation of the isoprostane a and of and oxidative stress D. J.A. J. The in and 2001; Scholar). demonstrate that levels were increased in and plasma as systemic as as directly within the of mice transplanted with sPLA2 transgenic bone marrow compared with to in vitro reported a of sPLA2 and 12/15-LO in the of S. D. of low density lipoprotein by phospholipase A2 oxidative Lipid Res. Scholar, J. R. phospholipase A2 and lipoprotein and in 1998; Scholar). in the of 12/15-LO and sPLA2 were to the oxidation of Notably, study sPLA2 as as sPLA2 S. D. of low density lipoprotein by phospholipase A2 oxidative Lipid Res. Scholar), the other study was with human type IIA sPLA2 J. R. phospholipase A2 and lipoprotein and in 1998; Scholar). the of sPLA2 to LDL a in the of the with oxidative S. D. of low density lipoprotein by phospholipase A2 oxidative Lipid Res. Scholar). 12/15-LO is expressed by and the from 12/15-LO mice significantly LDL oxidation D. of 12/15-lipoxygenase in of the and oxidation of low density Biol. Chem. Scholar). were in mice on a C57BL/6 that the sPLA2 as a of a P. J. P. M. A of the secretory group II phospholipase A2 gene in Biol. Chem. Scholar). is that the of human as in the transgenic in in a of LDL oxidation and the of oxidative This of sPLA2 and 12/15-LO is by the increased 12/15-LO protein levels that in the sPLA2 transgenic as as by the that 12/15-LO in sPLA2 transgenic with a the levels of in vitro LDL oxidation to in mice. on isoprostane data as as on the increased levels of 12/15-LO products within the of mice transplanted with the sPLA2 transgenic bone that is in to the of the between 12/15-LO and sPLA2 in the of increased oxidative stress the molecular Notably, was in et M.A. group IIA secretory phospholipase A2 increases atherosclerotic formation in LDL receptor-deficient Thromb. Vasc. Biol. reported that macrophage-specific of sPLA2 in increased atherosclerosis weeks of a Western-type with found that of sPLA2 in mice plasma cholesterol plasma sPLA2 and with to the reported of sPLA2 D. D.J. of secretory phospholipase A2 and of density lipoprotein and Biol. Chem. 2000; 275: Scholar, P.M. J. HDL by secretory phospholipase A2 type and HDL Lipid Res. 2000; Scholar, D. D.J. secretory phospholipase A2 (sPLA2) decreased plasma levels of and in response to inflammation of A in human transgenic Thromb. Vasc. Biol. 2002; Scholar, D.J. inflammation increases of HDL of mice human J. Scholar, phospholipase on lipoprotein Lipid Res. 1997; Scholar), study that the among lipoprotein in mice transplanted with bone marrow from sPLA2 transgenic mice compared with by for sPLA2 by atherogenesis in foam cell formation and increased LDL oxidation in vitro as as increased of oxidative stress in study that macrophage-specific overexpression of human sPLA2 increases atherogenesis in mice without systemic lipoprotein metabolism. data on the of sPLA2 by of sPLA2 in increased foam cell formation and of oxidative study that sPLA2 be a for inhibition as a atherosclerotic cardiovascular a of This was by from the the for to the of and to and to the of to and the to a in and

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