Our laboratory is interested in the regulation of inflammatory responses by phospholipid oxidation products. We have identified, using Mass Spectrometry and NMR, several phospholipid oxidation products that activate endothelial cell synthesis of inflammatory molecules. These phospholipid oxidation products are increased in cells exposed to oxidative stress and are increased upon feeding of a high fat diet. Current studies are focused on identifying the receptors for these lipids and the transcriptional and signal transduction pathways activated by them. For receptor identification, cDNA library screening and mass spec proteomics methods are being employed. Transcription studies employ promoter deletion analysis and EMSA. Signal transduction pathways are studied using cells from knock out mice, expression constructs and use of selective inhibitors. It is clear from our initial studies that phospholipid oxidation products act by mechanisms different from known stimulatory cytokines and Lipopolysaccharide. Our overall goal is to identify the novel pathways by which these oxidized phospholipids increase inflammation and to attempt to inhibit their action by knocking out or inhibiting these specific receptors or signaling pathways. In vivo receptor testing involving adenoviral overexpression of the receptors in vivo is currently being initiated.
Yeh M, Leitinger N et al
(2001).
Increased transcription of IL-8 in endothelial cells is differentially regulated by TNF alpha and oxidized phospholipids Arteriosclerosis, Thromb Vasc Biol
21:
1585-1591
Subbanagounder G, Wong JW et al
(2001).
Epoxyisoprostane and epoxycyclopentenone phospholipids regulate MCP-1 and IL-8 synthesis: formation of these oxidized lipids in response to IL-1 Beta Journal of Biological Chemistry
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Lee H, Shi W, Tontonoz P, Wang S, Subbanagounder G, Hedrick CC, Hama S, Borromeo C, Evans RM and Berliner JA.
(2000).
Role for Peroxisome Proliferator-Activated receptor alpha in oxidized phospholipid induced synthesis of monocyte chemotactic protein-1 and interleukin-8 by endothelial cells Circ Res
87:
516-521
Subbanagounder G, Leitinger N, Schwenke DC, Wong JW, Lee H, Rizza C, Watson AD, Faull KF, Fogelman AM and Berliner JA.
(2000).
Determinants of bioactivity of oxidized phospholipids Arterioscler Thromb Vasc Biol
20:
2248-2254
Shih PT, Elices MJ, Fang ZT, Ugarova TP, Strahl D, Territo MC, Frank JS, Kovach NL, Cabanas C, Berliner JA and Vora DK.
(1999).
MM-LDL induces monocyte adhesion to endothelial CS-1 by activating Beta 1 integrin J Clin Invest
103:
613-625
Watson AD, Subbanagounder G, Welsbie DS, Faull KF, Navab M, Jung ME, Fogelman AM and Berliner JA.
(1999).
Structural identification of a novel pro-inflammatory epoxy isoporostane phospholipid in mildly oxidized low density lipoprotein J Biol Chem
274:
24787-24798
Subbanagounder G, Leitinger N, Shih PT, Faull KF, Lee H and Berliner JA.
(1999).
Evidence that phospholipid oxidation products and/or platelet activating factor play an important role in early atherogenesis: In vitro and in vivo inhibition by WEB 2086 Circ Res
85:
311-318
Leitinger N, Tyner TR, Oslund L, Rizza C, Subbanagounder G, Lee H, Shih PT, Mackman N, Tigyi G, Territo MC, Berliner JA and Vora DK.
(1999).
Structurallly similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils Proc Natl Acad Sci
96:
12010-12015
Honda HM, Leitinger N, Frankel M, Goldhaber JI, Natarajan R, Weiss JN, Nadler J and Berliner JA.
(1999).
Induction of monocyte binding to endothelial cells by MM-LDL: the role of lipoxygenase metabolies Arterio Throm and Vasc Biol
19:
680-686
Leitinger N, Watson AD, Hama SY, Ivandic B, Qiao J, Huber J, Faull KF, Grass DS, Navab M, Fogelman AM, DeBeer F, Lusis A and Berliner JA.
(1999).
Rose of Group II secretory PLA2 in atherosclerosis Arterio Throm and Vasc Biol
19:
1291-1298
Shih PT, Brennan M, Vora DK, Territo MC, Strahl D, Elices MJ, Lusis AJ and Berliner JA.
(1999).
Blocking VLA-4 integrin decreases leukocyte entry and fatty streak formation in mice fed an atherogenic diet Circ Res
84:
345-351
Rizza C, Leitinger N, Junming Y, Fischer DJ, Wang D, Shih PT, Lee H, Tigyi G and Berliner JA
(1999).
Lysophosphatidic acid as a regulator of endothelial/leukocyte interaction Lab Invest
79:
1227-1235
Oslund LJP, Hedrick CC, Olvera T, Hagenbaugh A, Territo M, Berliner JA and Fyfe AI.
(1999).
Interleukin-10 blocks atherosclerotic events in vitro and in vivo Arterioscler Thromb Vasc Biol
19:
2847-2853
Honda HM, Leitinger N, Frankel M ...and Berliner JA
(1999).
Induction of monocyte binding to endothelial cells by MM-LDL; the role of lipoxygenase metabolites Arterio. Thromb and Vasc. Biol
In Press:
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Watson AD, Leitinger N, Navab M, Faull KF, Horkko S, Witztum JL, Palinski W, Schwenke D, Salomon RG, Sha W, Subbanagounder G, Fogelman AM and Berliner JA.
(1997).
Structual Identification by mass spectrometry of oxidized phospholipids in minimally oxidized LDL that induce monocyte/endothelial interactions and evidence for their presence in vivo J. Biol Chem
272:
13597-13607
Vora DK, Fang ZT, Liva SM, Tyner TR, Parhami F, Watson AD, Drake TA, Territo MC and Berliner JA.
(1997).
Induction of P-Selectin by oxidized lipoproteins-separate effects on synthesis and surface Expression Circ Res
80:
810-818
Watson AD, Leitinger N ....and Berliner JA
(1997).
Identification by Mass Spectrometry of Oxidized phospholipids in minimally oxidized LDL that induce monoocyte/endothelial intereactions and evidence for their presence in vivo J Biol Chem
272:
13597-13607
Watson AD, Leitinger N ....and Berliner JA
(1997).
Identification by Mass Spectrometry of Oxidized phospholipids in minimally oxidized LDL that induce monoocyte/endothelial intereactions and evidence for their presence in vivo J Biol Chem
272:
13597-13607
Watson AD, Leitinger N ....and Berliner JA
(1997).
Identification by Mass Spectrometry of Oxidized phospholipids in minimally oxidized LDL that induce monoocyte/endothelial intereactions and evidence for their presence in vivo J Biol Chem
272:
13597-13607
Watson AD, Leitinger N ....and Berliner JA
(1997).
Identification by Mass Spectrometry of Oxidized phospholipids in minimally oxidized LDL that induce monoocyte/endothelial intereactions and evidence for their presence in vivo J Biol Chem
272:
13597-13607
Watson, A.D., Berliner, J.A., Hama, S., La Du et al.
(1995).
Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of MM-LDL J Clin Invest
96:
2882-2891
Parhami, F., Fang, Z.T., Yang, B., Fogelman, A.M. and J.A. Berliner
(1995).
Stimulation of Gs and inhibition of Gi proteins functions by minimally oxidized LDL Arterioscler Throm Vasc Biol
15:
2019-2024
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Minimally modified LDL stimulates monocyte-endothelial interactions J Clin Invest
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