This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leitinger, N. Articles by Berliner, J. A. Search for Related Content PubMed PubMed Citation Articles by Leitinger, N. Articles by Berliner, J. A. Related Collections Animal models of human disease Pathophysiology Genetically altered mice Lipid and lipoprotein metabolism Oxidant stress

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1291-1298.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Role of Group II Secretory Phospholipase A₂ in Atherosclerosis

2. Potential Involvement of Biologically Active Oxidized Phospholipids

Norbert Leitinger; Andrew D. Watson; Susan Y. Hama; Boris Ivandic; Jian-Hua Qiao; Joakim Huber; Kym F. Faull; David S. Grass; Mohamad Navab; Alan M. Fogelman; Frederick C. de Beer; Aldons J. Lusis; Judith A. Berliner

From the Departments of Medicine (N.L., A.D.W., S.Y.H., B.I., J.-H.Q., J.H., M.N., A.M.F., A.J.L., J.A.B.), Pathology (N.L., J.A.B.), Psychiatry and Biobehavioral Sciences and the Neuropsychiatric Institute (K.M.F.), University of California, Los Angeles; Chrysalis DNX Transgenic Sciences (D.S.G.), Princeton, NJ; and the Department of Medicine (F.C.d.B.), University of Kentucky, Lexington. Current address for Norbert Leitinger, Department of Vascular Biology and Thrombosis Research, Schwarzspanierstrasse 17, A1090 Vienna, University of Vienna, Austria.

Correspondence to Judith A Berliner, 13-239 CHS, Departments of Pathology and Medicine, Los Angeles, CA 90095-1732. E-mail jberline{at}pathology.medsch.ucla.edu

Abstract—Secretory nonpancreatic phospholipase A₂ (group II sPLA₂) is induced in inflammation and present in atherosclerotic lesions. In an accompanying publication we demonstrate that transgenic mice expressing group II sPLA₂ developed severe atherosclerosis. The current study was undertaken to determine whether 1 mechanism by which group II sPLA₂ might contribute to the progression of inflammation and atherosclerosis is by increasing the formation of biologically active oxidized phospholipids. In vivo measurements of bioactive lipids were performed, and in vitro studies tested the hypothesis that sPLA₂ can increase the accumulation of bioactive phospholipids. We have shown previously that 3 oxidized phospholipids derived from the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) stimulated endothelial cells to bind monocytes, a process that is known to be an important step in atherogenesis. We now show that these 3 biologically active phospholipids are significantly increased in livers of sPLA₂ transgenic mice fed a high-fat diet as compared with nontransgenic littermates. We present in vitro evidence for several mechanisms by which these phospholipids may be increased in sPLA₂ transgenics. These studies demonstrated that polyunsaturated free fatty acids, which are liberated by sPLA₂, increased the formation of bioactive phospholipids in LDL, resulting in increased ability to stimulate monocyte-endothelial interactions. Moreover, sPLA₂-treated LDL was oxidized by cocultures of human aortic endothelial cells and smooth muscle cells more efficiently than untreated LDL. Analysis by electrospray ionization–mass spectrometry revealed that the bioactive phospholipids, compared with unoxidized PAPC, were less susceptible to hydrolysis by human recombinant group II sPLA₂. In addition, HDL from the transgenic mice and human HDL treated with recombinant sPLA₂ in vitro failed, in the coculture system, to protect against the formation of biologically active phospholipids in LDL. This lack of protection may in part relate to the decreased levels of paraoxonase seen in the HDL isolated from the transgenic animals. Taken together, these studies show that levels of biologically active oxidized phospholipids are increased in sPLA₂ transgenic mice; they also suggest that this increase may be mediated by effects of sPLA₂ on both LDL and HDL.

Key Words: mice, transgenic • lipid peroxidation • LDL oxidation • inflammation • spectrum analysis, mass • phospholipids

This article has been cited by other articles:

				M. S. Desai, M. M. Mariscalco, A. Tawil, J. G. Vallejo, and C. W. Smith Atherogenic diet-induced hepatitis is partially dependent on murine TLR4 J. Leukoc. Biol., June 1, 2008; 83(6): 1336 - 1344. [Abstract] [Full Text] [PDF]

				K. O. Badellino, M. L. Wolfe, M. P. Reilly, and D. J. Rader Endothelial Lipase Is Increased In Vivo by Inflammation in Humans Circulation, February 5, 2008; 117(5): 678 - 685. [Abstract] [Full Text] [PDF]

				N. A. Pidkovka, O. A. Cherepanova, T. Yoshida, M. R. Alexander, R. A. Deaton, J. A. Thomas, N. Leitinger, and G. K. Owens Oxidized Phospholipids Induce Phenotypic Switching of Vascular Smooth Muscle Cells In Vivo and In Vitro Circ. Res., October 12, 2007; 101(8): 792 - 801. [Abstract] [Full Text] [PDF]

				P. T.E. Wootton, N. L. Arora, F. Drenos, S. R. Thompson, J. A. Cooper, J. W. Stephens, S. J. Hurel, E. Hurt-Camejo, O. Wiklund, S. E. Humphries, et al. Tagging SNP haplotype analysis of the secretory PLA2-V gene, PLA2G5, shows strong association with LDL and oxLDL levels, suggesting functional distinction from sPLA2-IIA: results from the UDACS study Hum. Mol. Genet., June 15, 2007; 16(12): 1437 - 1444. [Abstract] [Full Text] [PDF]

				W. Koenig and N. Khuseyinova Biomarkers of Atherosclerotic Plaque Instability and Rupture Arterioscler. Thromb. Vasc. Biol., January 1, 2007; 27(1): 15 - 26. [Abstract] [Full Text] [PDF]

				A. Gutierrez, E. P. Ratliff, A. M. Andres, X. Huang, W. L. McKeehan, and R. A. Davis Bile Acids Decrease Hepatic Paraoxonase 1 Expression and Plasma High-Density Lipoprotein Levels Via FXR-Mediated Signaling of FGFR4 Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 301 - 306. [Abstract] [Full Text] [PDF]

				P. T.E. Wootton, F. Drenos, J. A. Cooper, S. R. Thompson, J. W. Stephens, E. Hurt-Camejo, O. Wiklund, S. E. Humphries, and P. J. Talmud Tagging-SNP haplotype analysis of the secretory PLA2IIa gene PLA2G2A shows strong association with serum levels of sPLA2IIa: results from the UDACS study Hum. Mol. Genet., January 15, 2006; 15(2): 355 - 361. [Abstract] [Full Text] [PDF]

				Z. Mallat, Ph. G. Steg, J. Benessiano, M.-L. Tanguy, K. A. Fox, J.-P. Collet, O. H. Dabbous, P. Henry, K. F. Carruthers, A. Dauphin, et al. Circulating Secretory Phospholipase A2 Activity Predicts Recurrent Events in Patients With Severe Acute Coronary Syndromes J. Am. Coll. Cardiol., October 4, 2005; 46(7): 1249 - 1257. [Abstract] [Full Text] [PDF]

				U. J. F. Tietge, D. Pratico, T. Ding, C. D. Funk, R. B. Hildebrand, T. Van Berkel, and M. Van Eck Macrophage-specific expression of group IIA sPLA2 results in accelerated atherogenesis by increasing oxidative stress J. Lipid Res., August 1, 2005; 46(8): 1604 - 1614. [Abstract] [Full Text] [PDF]

				S. M. Boekholdt, T. T. Keller, N. J. Wareham, R. Luben, S. A. Bingham, N. E. Day, M. S. Sandhu, J. W. Jukema, J. J.P. Kastelein, C. E. Hack, et al. Serum Levels of Type II Secretory Phospholipase A2 and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women: The EPIC-Norfolk Prospective Population Study Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 839 - 846. [Abstract] [Full Text] [PDF]

				C. Iribarren, M. D. Gross, J. A. Darbinian, D. R. Jacobs Jr, S. Sidney, and C. M. Loria Association of Lipoprotein-Associated Phospholipase A2 Mass and Activity With Calcified Coronary Plaque in Young Adults: The CARDIA Study Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 216 - 221. [Abstract] [Full Text] [PDF]

				J. Oestvang, D. Bonnefont-Rousselot, E. Ninio, J. K. Hakala, B. Johansen, and M. W. Anthonsen Modification of LDL with human secretory phospholipase A2 or sphingomyelinase promotes its arachidonic acid-releasing propensity J. Lipid Res., May 1, 2004; 45(5): 831 - 838. [Abstract] [Full Text] [PDF]

				P. E. Szmitko, C.-H. Wang, R. D. Weisel, G. A. Jeffries, T. J. Anderson, and S. Verma Biomarkers of Vascular Disease Linking Inflammation to Endothelial Activation: Part II Circulation, October 28, 2003; 108(17): 2041 - 2048. [Full Text] [PDF]

				H. W.M Niessen, P. A.J Krijnen, C. A Visser, C. J.L.M Meijer, and C Erik Hack Type II secretory phospholipase A2 in cardiovascular disease: a mediator in atherosclerosis and ischemic damage to cardiomyocytes? Cardiovasc Res, October 15, 2003; 60(1): 68 - 77. [Abstract] [Full Text] [PDF]

				P.-Y. Liu, Y.-H. Li, W.-C. Tsai, T.-H. Chao, L.-M. Tsai, H.-L. Wu, and J.-H. Chen Prognostic value and the changes of plasma levels of secretory type II phospholipase A2 in patients with coronary artery disease undergoing percutaneous coronary intervention Eur. Heart J., October 2, 2003; 24(20): 1824 - 1832. [Abstract] [Full Text] [PDF]

				B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]

				A. A. Spector Plaque Rupture, Lysophosphatidic Acid, and Thrombosis Circulation, August 12, 2003; 108(6): 641 - 643. [Full Text] [PDF]

				K. A. Walton, X. Hsieh, N. Gharavi, S. Wang, G. Wang, M. Yeh, A. L. Cole, and J. A. Berliner Receptors Involved in the Oxidized 1-Palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine-mediated Synthesis of Interleukin-8: A ROLE FOR TOLL-LIKE RECEPTOR 4 AND A GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED PROTEIN J. Biol. Chem., August 8, 2003; 278(32): 29661 - 29666. [Abstract] [Full Text] [PDF]

				N. R. Webb, M. A. Bostrom, S. J. Szilvassy, D. R. van der Westhuyzen, A. Daugherty, and F. C. de Beer Macrophage-Expressed Group IIA Secretory Phospholipase A2 Increases Atherosclerotic Lesion Formation in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 263 - 268. [Abstract] [Full Text] [PDF]

				S. Eligini, M. Brambilla, C. Banfi, M. Camera, L. Sironi, S. S. Barbieri, J. Auwerx, E. Tremoli, and S. Colli Oxidized phospholipids inhibit cyclooxygenase-2 in human macrophages via nuclear factor-{kappa}B/I{kappa}B- and ERK2-dependent mechanisms Cardiovasc Res, August 1, 2002; 55(2): 406 - 415. [Abstract] [Full Text] [PDF]

				J. Huber, A. Vales, G. Mitulovic, M. Blumer, R. Schmid, J. L. Witztum, B. R. Binder, and N. Leitinger Oxidized Membrane Vesicles and Blebs From Apoptotic Cells Contain Biologically Active Oxidized Phospholipids That Induce Monocyte-Endothelial Interactions Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 101 - 107. [Abstract] [Full Text] [PDF]

				P. K. Shah, S. Kaul, J. Nilsson, and B. Cercek Exploiting the Vascular Protective Effects of High-Density Lipoprotein and Its Apolipoproteins: An Idea Whose Time for Testing Is Coming, Part I Circulation, November 6, 2001; 104(19): 2376 - 2383. [Full Text] [PDF]

				N. Petrovic, C. Grove, P. E. Langton, N. L. A. Misso, and P. J. Thompson A simple assay for a human serum phospholipase A2 that is associated with high-density lipoproteins J. Lipid Res., October 1, 2001; 42(10): 1706 - 1714. [Abstract] [Full Text] [PDF]

				A. MERTENS and P. HOLVOET Oxidized LDL and HDL: antagonists in atherothrombosis FASEB J, October 1, 2001; 15(12): 2073 - 2084. [Abstract] [Full Text] [PDF]

				E. Hurt-Camejo, G. Camejo, H. Peilot, K. Oorni, and P. Kovanen Phospholipase A2 in Vascular Disease Circ. Res., August 17, 2001; 89(4): 298 - 304. [Abstract] [Full Text] [PDF]

				M. Navab, S. Y. Hama, G. P. Hough, G. Subbanagounder, S. T. Reddy, and A. M. Fogelman A cell-free assay for detecting HDL that is dysfunctional in preventing the formation of or inactivating oxidized phospholipids J. Lipid Res., August 1, 2001; 42(8): 1308 - 1317. [Abstract] [Full Text] [PDF]

				C. L. Welch, S. Bretschger, N. Latib, M. Bezouevski, Y. Guo, N. Pleskac, C.-P. Liang, C. Barlow, H. Dansky, J. L. Breslow, et al. Localization of atherosclerosis susceptibility loci to chromosomes 4 and 6 using the Ldlr knockout mouse model PNAS, July 3, 2001; 98(14): 7946 - 7951. [Abstract] [Full Text] [PDF]

				M. Navab, J. A. Berliner, G. Subbanagounder, S. Hama, A. J. Lusis, L. W. Castellani, S. Reddy, D. Shih, W. Shi, A. D. Watson, et al. HDL and the Inflammatory Response Induced by LDL-Derived Oxidized Phospholipids Arterioscler. Thromb. Vasc. Biol., April 1, 2001; 21(4): 481 - 488. [Abstract] [Full Text] [PDF]

				C. J. Packard, D. S.J. O'Reilly, M. J. Caslake, A. D. McMahon, I. Ford, J. Cooney, C. H. Macphee, K. E. Suckling, M. Krishna, F. E. Wilkinson, et al. Lipoprotein-Associated Phospholipase A2 as an Independent Predictor of Coronary Heart Disease N. Engl. J. Med., October 19, 2000; 343(16): 1148 - 1155. [Abstract] [Full Text] [PDF]

				W. Pruzanski, E. Stefanski, F. C. de Beer, M. C. de Beer, A. Ravandi, and A. Kuksis Comparative analysis of lipid composition of normal and acute-phase high density lipoproteins J. Lipid Res., July 1, 2000; 41(7): 1035 - 1047. [Abstract] [Full Text]

				M. Mietus-Snyder, M. S. Gowri, and R. E. Pitas Class A Scavenger Receptor Up-regulation in Smooth Muscle Cells by Oxidized Low Density Lipoprotein. ENHANCEMENT BY CALCIUM FLUX AND CONCURRENT CYCLOOXYGENASE-2 UP-REGULATION J. Biol. Chem., June 2, 2000; 275(23): 17661 - 17670. [Abstract] [Full Text] [PDF]

				P. T. Kovanen and M. O. Pentikainen Secretory Group II Phospholipase A2 : A Newly Recognized Acute-Phase Reactant With a Role in Atherogenesis Circ. Res., March 31, 2000; 86(6): 610 - 612. [Full Text] [PDF]

				P. Sartipy, B. Johansen, K. Gasvik, and E. Hurt-Camejo Molecular Basis for the Association of Group IIA Phospholipase A2 and Decorin in Human Atherosclerotic Lesions Circ. Res., March 31, 2000; 86(6): 707 - 714. [Abstract] [Full Text] [PDF]

				S. Parthasarathy, N. Santanam, S. Ramachandran, and O. Meilhac Oxidants and antioxidants in atherogenesis: an appraisal J. Lipid Res., December 1, 1999; 40(12): 2143 - 2157. [Abstract] [Full Text] [PDF]

				N. Leitinger, T. R. Tyner, L. Oslund, C. Rizza, G. Subbanagounder, H. Lee, P. T. Shih, N. Mackman, G. Tigyi, M. C. Territo, et al. Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils PNAS, October 12, 1999; 96(21): 12010 - 12015. [Abstract] [Full Text] [PDF]

				P. Sartipy, G. Camejo, L. Svensson, and E. Hurt-Camejo Phospholipase A2 Modification of Low Density Lipoproteins Forms Small High Density Particles with Increased Affinity for Proteoglycans and Glycosaminoglycans J. Biol. Chem., September 3, 1999; 274(36): 25913 - 25920. [Abstract] [Full Text] [PDF]

				B. Ivandic, L. W. Castellani, X.-P. Wang, J.-H. Qiao, M. Mehrabian, M. Navab, A. M. Fogelman, D. S. Grass, M. E. Swanson, M. C. de Beer, et al. Role of Group II Secretory Phospholipase A2 in Atherosclerosis : 1. Increased Atherogenesis and Altered Lipoproteins in Transgenic Mice Expressing Group IIa Phospholipase A2 Arterioscler. Thromb. Vasc. Biol., May 1, 1999; 19(5): 1284 - 1290. [Abstract] [Full Text] [PDF]

				B. J. Van Lenten, A. C. Wagner, M. Navab, and A. M. Fogelman Oxidized Phospholipids Induce Changes in Hepatic Paraoxonase and ApoJ but Not Monocyte Chemoattractant Protein-1 via Interleukin-6 J. Biol. Chem., January 12, 2001; 276(3): 1923 - 1929. [Abstract] [Full Text] [PDF]

				M. Murakami, R. S. Koduri, A. Enomoto, S. Shimbara, M. Seki, K. Yoshihara, A. Singer, E. Valentin, F. Ghomashchi, G. Lambeau, et al. Distinct Arachidonate-releasing Functions of Mammalian Secreted Phospholipase A2s in Human Embryonic Kidney 293 and Rat Mastocytoma RBL-2H3 Cells through Heparan Sulfate Shuttling and External Plasma Membrane Mechanisms J. Biol. Chem., March 23, 2001; 276(13): 10083 - 10096. [Abstract] [Full Text] [PDF]

				J. Boren, A. Lookene, E. Makoveichuk, S. Xiang, M. Gustafsson, H. Liu, P. Talmud, and G. Olivecrona Binding of Low Density Lipoproteins to Lipoprotein Lipase Is Dependent on Lipids but Not on Apolipoprotein B J. Biol. Chem., July 13, 2001; 276(29): 26916 - 26922. [Abstract] [Full Text] [PDF]

				S. Reddy, S. Hama, V. Grijalva, K. Hassan, R. Mottahedeh, G. Hough, D. J. Wadleigh, M. Navab, and A. M. Fogelman Mitogen-activated Protein Kinase Phosphatase 1 Activity Is Necessary for Oxidized Phospholipids to Induce Monocyte Chemotactic Activity in Human Aortic Endothelial Cells J. Biol. Chem., May 11, 2001; 276(20): 17030 - 17035. [Abstract] [Full Text] [PDF]

				T. M. Stulnig, J. Huber, N. Leitinger, E.-M. Imre, P. Angelisova, P. Nowotny, and W. Waldhausl Polyunsaturated Eicosapentaenoic Acid Displaces Proteins from Membrane Rafts by Altering Raft Lipid Composition J. Biol. Chem., September 28, 2001; 276(40): 37335 - 37340. [Abstract] [Full Text] [PDF]

				D. M. Shih, Y.-R. Xia, X.-P. Wang, E. Miller, L. W. Castellani, G. Subbanagounder, H. Cheroutre, K. F. Faull, J. A. Berliner, J. L. Witztum, et al. Combined Serum Paraoxonase Knockout/Apolipoprotein E Knockout Mice Exhibit Increased Lipoprotein Oxidation and Atherosclerosis J. Biol. Chem., June 2, 2000; 275(23): 17527 - 17535. [Abstract] [Full Text] [PDF]