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Hypochlorite-oxidized low-density lipoprotein upregulates CD36 and PPARγ mRNA expression and modulates SR-BI gene expression in murine macrophages

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Abstract

The uptake of oxidized low-density lipoprotein (oxLDL) by scavenger receptors of macrophages with resulting foam cell formation is considered a critical event in atherogenesis. Since hypochlorite-oxidized LDL (HOCl-LDL) has been shown to be recognized by macrophages and evidence was provided that HOCl-LDL is internalized via class B scavenger receptors CD36 and SR-BI, the regulatory relationships between CD36, SR-BI, and the nuclear transcription factor PPARγ in murine macrophages (RAW 264.7) on exposure to HOCl-LDL were examined. Using the highly sensitive real-time RT-PCR we could demonstrate that HOCl-LDL upregulated CD36 and PPARγ levels dose- and time dependently while modulating SR-BI message levels differently in dependence on HOCl-LDL concentration and incubation time. On exposure of macrophages to HOCl-LDL but not native LDL in varying concentrations, a significant positive correlation between CD36 and PPARγ (ρ = 0.603, p = 0.001) was observed indicating the presence of a positive feedback mechanism by which HOCl-LDL could promote its own uptake. The transcriptional expression of SR-BI in macrophages was not significantly related to PPARγ mRNA levels after treatment with HOCl-LDL suggesting a differential regulation of the two members of the scavenger receptor class B family in response to HOCl-LDL.

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References

  1. Hazen SL, Heinecke JW: 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J Clin Invest 99: 2075–2081, 1997

    PubMed  Google Scholar 

  2. Thukkani AK, McHowat J, Hsu FF, Brennan ML, Hazen SL, Ford DA: Identification of alpha-chloro fatty aldehydes and unsaturated lysophosphatidylcholine molecular species in human atherosclerotic lesions. Circulation 108: 3128–3133, 2003

    Article  PubMed  Google Scholar 

  3. Malle E, Waeg G, Schreiber R, Grone EF, Sattler W, Grone HJ: Immunohistochemical evidence for the myeloperoxidase/H2O2/halide system in human atherosclerotic lesions: colocalization of myeloperoxidase and hypochlorite-modified proteins. Eur J Biochem 267: 4495–503, 2000

    Article  PubMed  Google Scholar 

  4. Hazell LJ, Stocker R: Oxidation of low-density lipoprotein with hypochlorite causes transformation of the lipoprotein into a high-uptake form for macrophages. Biochem J 290: 165–172, 1993

    PubMed  Google Scholar 

  5. Kopprasch S, Leonhardt W, Pietzsch J, Kühne H: Hypochlorite-modified low-density lipoprotein stimulates human polymorphonuclear leukocytes for enhanced production of reactive oxygen metabolites, enzyme secretion, and adhesion to endothelial cells. Atherosclerosis 136: 315–324, 1998.

    Article  PubMed  Google Scholar 

  6. Kopprasch S, Pietzsch J, Westendorf T, Kruse HJ, Graessler J: The pivotal role of scavenger receptor CD36 and phagocyte-derived oxidants in oxidized low density lipoprotein-induced adhesion to endothelial cells. Int J Biochem Cell Biol 36: 460–471, 2004

    Article  PubMed  Google Scholar 

  7. Krieger M: Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems. J Clin Invest 108: 793–797, 2001

    Article  PubMed  Google Scholar 

  8. Nicholson AC, Frieda S, Pearce A, Silverstein RL: Oxidized LDL binds to CD36 on human monocyte-derived macrophages and transfected cell lines. Evidence implicating the lipid moiety of the lipoprotein as the binding site. Arterioscler Thromb Vasc Biol 15: 269–75, 1995

    PubMed  Google Scholar 

  9. Marsche G, Zimmermann R, Horiuchi S, Tandon NN, Sattler W, Malle E: Class B scavenger receptors CD36 and SR-BI are receptors for hypochlorite-modified low density lipoprotein. J Biol Chem 278: 47562–47570, 2003

    Article  PubMed  Google Scholar 

  10. Feng J, Han J, Pearce SF, Silverstein RL, Gotto AM Jr, Hajjar DP, Nicholson AC: Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma. J Lipid Res 41: 688–696, 2000

    PubMed  Google Scholar 

  11. Kavanagh IC, Symes CE, Renaudin P, Nova E, Mesa MD, Boukouvalas G, Leake DS, Yaqoob P: Degree of oxidation of low density lipoprotein affects expression of CD36 and PPARgamma, but not cytokine production, by human monocyte-macrophages. Atherosclerosis 168: 271–282, 2003

    Article  PubMed  Google Scholar 

  12. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM: Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93: 229–240, 1998

    Article  PubMed  Google Scholar 

  13. Jiang C, Ting AT, Seed B: PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391: 82–86, 1998

    Article  PubMed  Google Scholar 

  14. Chinetti G, Gbaguidi FG, Griglio S, Mallat Z, Antonucci M, Poulain P, Chapman J, Fruchart JC, Tedgui A, Najib-Fruchart J, Staels B: CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation 101: 2411–2417, 2000

    PubMed  Google Scholar 

  15. Pietzsch J, Subat S, Nitzsche S, Leonhardt W, Schentke KU, Hanefeld M: Very fast ultracentrifugation of serum lipoproteins: influence on lipoprotein separation and composition. Biochim Biophys Acta 1254: 77–88, 1995

    PubMed  Google Scholar 

  16. Shoji T, Nishizawa Y, Fukumoto M, Shimamura K, Kimura J, Kanda H, Emoto M, Kawagishi T, Morii H: Inverse relationship between circulating oxidized low density lipoprotein (oxLDL) and anti-oxLDL antibody levels in healthy subjects. Atherosclerosis 148: 171–177, 2000

    Article  PubMed  Google Scholar 

  17. Hazell LJ, Arnold L, Flowers, D, Waeg G, Malle E, Stocker R: Presence of hypochlorite-modified proteins in human atherosclerotic lesions. J Clin Invest 97: 1535–1544, 1996

    PubMed  Google Scholar 

  18. Savill J, Hogg N, Haslett C: Macrophage vitronectin receptor, CD36, and thrombospondin cooperate in recognition of neutrophils undergoing programme cell death. Chest 99: 6S–7S, 1991

    Google Scholar 

  19. Abumrad NA, el-Maghrabi MR, Amri EZ, Lopez E, Grimaldi PA: Cloning of a rat adipocyte membrane protein implicated in binding or transport of long-chain fatty acids that is induced during preadipocyte differentiation. Homology with human CD36. J Biol Chem 268: 17665–17668, 1993

    PubMed  Google Scholar 

  20. Febbraio M, Hajjar DP, Silverstein RL: CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 108: 785–791, 2001

    Article  PubMed  Google Scholar 

  21. Hirano K, Yamashita S, Nakagawa Y, Ohya T, Matsuura F, Tsukamoto K, Okamoto Y, Matsuyama A, Matsumoto K, Miyagawa J, Matsuzawa Y: Expression of human scavenger receptor class B type I in cultured human monocyte-derived macrophages and atherosclerotic lesions. Circ Res 85: 108–116, 1999

    PubMed  Google Scholar 

  22. Rhainds D, Brissette L: The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. Defining the rules for lipid traders. Int J Biochem Cell Biol 36: 39–77, 2004

    Article  PubMed  Google Scholar 

  23. Van Eck M, Bos IS, Hildebrand RB, Van Rij BT, Van Berkel TJC: Dual role for scavenger receptor class B, type I on bone marrow-derived cells in atherosclerotic lesion development. Am J Pathol 165: 785–794, 2004

    PubMed  Google Scholar 

  24. Han J, Nicholson AC, Zhou X, Feng J, Gotto AM Jr, Hajjar DP: Oxidized low density lipoprotein decreases macrophage expression of scavenger receptor B-I. J Biol Chem 276: 16567–16572, 2001

    Article  PubMed  Google Scholar 

  25. Yu L, Cao G, Repa J, Stangl H: Sterol regulation of scavenger receptor class B type I in macrophages. J Lipid Res 45: 889–899, 2004

    Article  PubMed  Google Scholar 

  26. Lam MCW, Tan KCB, Lam KSL: Glycoxidized low-density lipoprotein regulates the expression of scavenger receptors in THP-1 macrophages. Atherosclerosis 177: 313–320, 2004

    Article  PubMed  Google Scholar 

  27. Plutzky J: Peroxisome proliferator-activated receptors in vascular biology and atherosclerosis: emerging insights for evolving paradigm. Curr Atheroscler Rep 2: 327–335, 2000

    PubMed  Google Scholar 

  28. Collins AR, Meehan WP, Kintscher U, Jackson S, Wakino S, Noh G, Palinski W, Hsueh WA, Law RE: Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 21: 365–371, 2001

    PubMed  Google Scholar 

  29. Argmann CA, Sawyez CG, McNeil CJ, Hegele RA, Huff WM: Activation of peroxisome proliferator-activated receptor gamma and retinoid X receptor results in net depletion of cellular cholesteryl esters in macrophages exposed to oxidized lipoprotein. Arterioscler Thromb Vasc Biol 23: 475–482, 2003

    Article  PubMed  Google Scholar 

  30. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM: PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93: 241–252, 1998

    Article  PubMed  Google Scholar 

  31. Malerod L, Sporstol M, Juvet LK, Mousavi A, Gjoen T, Berg T: Hepatic scavenger receptor class B, type I is stimulated by peroxisome proliferator-activated receptor gamma and hepatocytes nuclear factor 4alpha. Biochem Biophys Res Commun 305: 557–565, 2003

    Article  PubMed  Google Scholar 

  32. Malerod L, Juvet LK, Hanssen-Bauer A, Eskild W, Berg T: Oxysterol-activated LXRalpha/RXR induces hSR-BI-promoter activity in hepatoma cells and preadipocytes. Biochem Biophys Res Commun 299: 916–923, 2002

    Article  PubMed  Google Scholar 

  33. Lopez D, McLean MP: Sterol regulatory element-binding protein-1a binds to cis elements in the promoter of the rat high density lipoprotein receptor SR-BI gene. Endocrinology 140: 5669–5681, 1999

    Article  PubMed  Google Scholar 

  34. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM: PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 7: 48–52, 2001

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine III, Pathological Biochemistry, Carl Gustav Carus Medical School, University of Technology, Fetscherstr. 74, 01307, Dresden, Germany

    Thomas Westendorf, Juergen Graessler & Steffi Kopprasch

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  1. Thomas Westendorf
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  2. Juergen Graessler
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  3. Steffi Kopprasch
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Correspondence to Steffi Kopprasch.

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Westendorf, T., Graessler, J. & Kopprasch, S. Hypochlorite-oxidized low-density lipoprotein upregulates CD36 and PPARγ mRNA expression and modulates SR-BI gene expression in murine macrophages. Mol Cell Biochem 277, 143–152 (2005). https://doi.org/10.1007/s11010-005-5873-z

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  • DOI: https://doi.org/10.1007/s11010-005-5873-z

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