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Degree of oxidation of low density lipoprotein affects expression of CD36 and PPARγ, but not cytokine production, by human monocyte-macrophages

      Abstract

      Oxidized low-density lipoprotein (oxLDL) exhibits many atherogenic effects, including the promotion of monocyte recruitment to the arterial endothelium and the induction of scavenger receptor expression. However, while atherosclerosis involves chronic inflammation within the arterial intima, it is unclear whether oxLDL alone provides a direct inflammatory stimulus for monocyte-macrophages. Furthermore, oxLDL is not a single, well-defined entity, but has structural and physical properties which vary according to the degree of oxidation. We tested the hypothesis that the biological effects of oxLDL will vary according to its degree of oxidation and that some species of oxLDL will have atherogenic properties, while other species may be responsible for its inflammatory activity. The atherogenic and inflammatory properties of LDL oxidized to predetermined degrees (mild, moderate and extensive oxidation) were investigated in a single system using human monocyte-derived macrophages. Expression of CD36 mRNA was up-regulated by mildly- and moderately-oxLDL, but not highly-oxLDL. The expression of the transcription factor, proliferator-activated receptor-γ (PPARγ), which has been proposed to positively regulate the expression of CD36, was increased to the greatest degree by highly-oxLDL. However, the DNA binding activity of PPARγ was increased only by mildly- and moderately-oxLDL. None of the oxLDL species appeared to be pro-inflammatory towards monocytes, either directly or indirectly through mediators derived from lymphocytes, regardless of the degree of oxidation.

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      References

        • Febbraio M.
        • Podrez E.A.
        • Smith J.D.
        • et al.
        Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.
        J. Clin. Invest. 2000; 105: 1049-1056
        • Huh H.Y.
        • Pearce S.F.
        • Yesner L.M.
        • Schindler J.L.
        • Silverstein R.L.
        Regulated expression of CD36 during monocyte-to-macrophage differentiation: potential role of CD36 in foam cell formation.
        Blood. 1996; 87: 2020-2028
        • Nagy L.
        • Tontonoz P.
        • Alvarez J.G.A.
        • Chen H.
        • Evans R.M.
        Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ.
        Cell. 1998; 93: 229-240
        • Tontonoz P.
        • Nagy L.
        • Alvarez J.G.A.
        • Thomazy V.A.
        • Evans R.M.
        PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL.
        Cell. 1998; 93: 241-252
        • Ricote M.
        • Li A.C.
        • Wilson T.M.
        • Kelly C.J.
        • Glass C.K.
        The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage function.
        Nature. 1998; 391: 79-82
        • Chawla A.
        • Barak Y.
        • Nagy L.
        • Liao D.
        • Tontonoz P.
        • Evans R.M.
        PPARγ dependent and independent effects on macrophage gene expression in lipid metabolism and inflammation.
        Nat. Med. 2001; 7: 48-52
        • Chinetti G.
        • Lestavel S.
        • Bocher V.
        • et al.
        PPARα and PPARγ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.
        Nat. Med. 2001; 7: 53-58
        • Patel L.
        • Charlton S.J.
        • Marshall I.C.
        • et al.
        PPARγ is not a critical mediator of primary monocyte differentiation or foam cell formation.
        Biochem. Biophys. Res. Commun. 2002; 290: 707-712
        • Jiang C.
        • Ting A.T.
        • Seed B.
        PPARγ agonists inhibit production of monocyte inflammatory cytokines.
        Nature. 1998; 391: 82-86
        • Thieringer R.
        • Fenyk-Melody J.E.
        • Le Grand C.B.
        • et al.
        Activation of peroxisome proliferator-activated receptor γ does not inhibit IL-6 or TNFα responses of macrophages to lipopolysaccharide in vitro or in vivo.
        J. Immunol. 2000; 164: 1046-1054
        • Vaidya S.
        • Somers E.P.
        • Wright S.D.
        • Detmers P.A.
        • Bansal V.S.
        15-Deoxy prostaglandin J2 inhibits the β2 integrin-dependent oxidative burst: involvement of a mechanism distinct from peroxisome proliferator-activated receptor-γ ligation.
        J. Immunol. 1999; 163: 6187-6192
        • Ross R.
        Mechanisms of disease—atherosclerosis—an inflammatory disease.
        New Engl. J. Med. 1999; 340: 115-126
        • Berliner J.A.
        • Territo M.C.
        • Sevanian A.
        • et al.
        Minimally modified low density lipoprotein stimulates monocyte endothelial interactions.
        J. Clin. Invest. 1990; 85: 1260-1266
        • Hamilton T.A.
        • Major J.A.
        • Chisolm G.M.
        The effects of oxidized low density lipoproteins on inducible mouse macrophage gene expression are gene and stimulus dependent.
        J. Clin. Invest. 1995; 95: 2020-2027
        • Brand K.
        • Banka C.L.
        • Mackman N.
        • Terkeltaub R.A.
        • Fan S.-T.
        • Curtiss L.K.
        Oxidized LDL enhances lipopolysaccharide-induced tissue factor expression in human adherent monocytes.
        Arterioscler. Thromb. Vasc. Biol. 1994; 14: 790-797
        • Hamilton T.A.
        • Ma G.
        • Chisolm G.M.
        Oxidized low-density lipoprotein suppresses the expression of tumor necrosis factor-alpha mRNA in stimulated murine peritoneal macrophages.
        J. Immunol. 1990; 144: 2343-2350
        • Mikita T.
        • Porter G.
        • Lawn R.M.
        • Shiffman D.
        Oxidized low density lipoprotein exposure alters the transcriptional response of macrophages to inflammatory stimulus.
        J. Biol. Chem. 2001; 276: 45729-45739
        • Glass C.K.
        • Witzum J.L.
        Atherosclerosis: the road ahead.
        Cell. 2001; 104: 503-516
        • Rice-Evans C.
        • Leake D.S.
        • Bruckdorfer K.R.
        • Diplock A.T.
        Practical approaches to low density lipoprotein oxidation—whys wherefores and pitfalls.
        Free Radic. Res. 1996; 25: 285-311
        • Yoshida H.
        • Quehenberger O.
        • Kondratenko N.
        • Green S.
        • Steinberg D.
        Minimally oxidized low-density lipoprotein increases expression of the scavenger receptor A, CD36 and macrosialin in resident mouse peritoneal macrophages.
        Arterioscler. Thromb. Vasc. Biol. 1998; 18: 794-802
        • Siow R.C.M.
        • Richards J.P.
        • Pedley K.C.
        • Leake D.S.
        • Mann G.
        Vitamin C protects human vascular smooth muscle cells against apoptosis by moderately oxidized LDL containing high levels of lipid hydroperoxides.
        Arterioscler. Thromb. Vasc. Biol. 1999; 19: 2387-2394
        • Gomez-Munoz A.
        • Martens J.S.
        • Steinbrecher U.P.
        Stimulation of phospholipase D activity by oxidized LDL in mouse peritoneal macrophages.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 135-143
        • El-Saadani M.
        • Esterbauer H.
        • El-Sayed M.
        • Gohe M.
        • Nassar A.Y.
        • Jurgens G.
        A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent.
        J. Lipid Res. 1989; 30: 627-630
        • Borenfreund E.
        • Babich H.
        • Martinalguacil N.
        Rapid chemosensitivity assay with human normal and tumor cells in vitro.
        In Vitro Cell Dev. Biol. 1990; 20: 1030-1034
        • Watson A.D.
        • Leitinger N.
        • Navab M.
        • et al.
        Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo.
        J. Biol. Chem. 1997; 272: 13597-13607
        • Leitinger N.
        • Tyner T.R.
        • Oslund L.
        • et al.
        Structurally similar oxidized phospholipids differentially regulate endothelial binding of monocytes and neutrophils.
        Proc. Natl. Acad. Sci. USA. 1999; 96: 12010-12015
        • Subbanagounder G.
        • Leitinger N.
        • Schwenke D.C.
        • et al.
        Determinants of bioactivity of oxidized phospholipids-specific oxidized fatty acyl groups at the sn-2 position.
        Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2248-2254
        • Carpenter K.H.
        • Wilkins G.M.
        • Fussell B.
        • Ballantine J.A.
        • Taylor S.E.
        • Mitchinson M.J.
        • Leake D.S.
        Production of oxidized lipids during modification of low-density lipoprotein by macrophages or copper.
        Biochem. J. 1994; 304: 625-633
        • Dominaitiene R.
        • Lindgren S.
        • Janciauskiene S.
        Effects of differentially oxidized LDL on the expression of pro-inflammatory molecules in human monocytes in vitro.
        In Vitro Molec. Toxicol. 2001; 14: 83-97
        • Wang T.
        • Yu W.-G.
        • Powell W.S.
        Formation of monohydroxy derivatives of arachidonic acid, linoleic acid and oleic acid during oxidation of low density lipoprotein by copper ions and endothelial cells.
        J. Lipid Res. 1992; 33: 525-537
        • Fajas L.
        • Auboeuf D.
        • Raspe E.
        • et al.
        The organization, promoter analysis and expression of the human PPARγ gene.
        J. Biol. Chem. 1997; 272: 18779-18789
        • Chung S.W.
        • Kang B.Y.
        • Kim S.Y.
        • Pak Y.K.
        • Cho D.
        • Trincheri G.
        • Kim T.S.
        Oxidized low-density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor gamma and nuclear factor kappa B.
        J. Biol. Chem. 2000; 275: 32681-32687
        • Sato O.
        • Kuriki C.
        • Fukui Y.
        • Motojima K.
        Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor α and γ ligands.
        J. Biol. Chem. 2002; 277: 15703-15711
        • Stengel D.
        • Antonucci M.
        • Arborati M.
        • Hourton D.
        • Griglio S.
        • Chapman M.J.
        • Ninio E.
        Expression of PAF receptor in human monocyte-derived macrophages is down-regulated by oxidized LDL.
        Arterioscler. Thromb. Vasc. Biol. 1997; 17: 954-962
        • Hourton D.
        • Delerive P.
        • Stankova J.
        • Staels B.
        • Chapman A.J.
        • Ninio E.
        Oxidized low-density lipoprotein and peroxisome-proliferator-activated receptor α down-regulate platelet-activating factor receptor expression in human macrophages.
        Biochem. J. 2001; 354: 225-232
        • Marx N.
        • Sukhova G.
        • Murphy C.
        • Libby P.
        • Plutzky J.
        Macrophages in human atheroma contain PPARγ. Differentiation-dependent peroxisomal proliferator-activated receptor γ expression and reduction of MMP-9 activity through PPARγ activation in mononuclear phagocytes in vitro.
        Am. J. Pathol. 1998; 153: 17-23
        • Caspar-Baugil S.
        • Tkaczuk J.
        • Haure M.-J.
        • et al.
        Mildly oxidized low-density lipoproteins decrease early production of interleukin-2 and nuclear factor kB binding to DNA in activated T-lymphocytes.
        Biochem. J. 1999; 337: 269-274
        • Alcouffe J.
        • Caspar-Bauguil S.
        • Garcia V.
        • Salvayre R.
        • Thomsen M.
        • Benoist H.
        Oxidized low density lipoproteins induce apoptosis in PHA-activated peripheral blood mononuclear cells and in the Jurkat cell line.
        J. Lipid Res. 1999; 40: 1200-1210