α-Tocopherol decreases CD36 expression in human monocyte-derived macrophages

Abstract

Cholesterol-laden macrophages are the hallmark of atherogenesis. The class B scavenger receptor, CD36, binds oxidized low density lipoprotein (OxLDL), is found in atherosclerotic lesions, and is upregulated by OxLDL. We tested the effects of α-tocopherol (AT) enrichment of human monocyte-derived macrophages on CD36 expression and cholesteryl ester accumulation. Monocytes isolated from normal volunteers were cultured into macrophages. Macrophages were enriched overnight with various doses of AT (25, 50, and 100 μM). LDL from normal volunteers was oxidized or acetylated (AcLDL) and incubated with macrophages for 48 h at a concentration of 50 or 100 μg/ml. CD36 expression was assessed by flow cytometry. Quantitative analysis of scavenger receptor class A (SR-A) activity was performed with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanide perchlorate (DiI)-labeled LDL. CD36 expression was maximal after 8–10 days of culture. AT (≥50 μM) significantly decreased CD36 expression upregulated by OxLDL and AcLDL (P < 0.01). Other antioxidants (β- or γ-tocopherol) or protein kinase C inhibitors failed to decrease CD36 expression. Concomitantly, DiI-AcLDL and DiI-OxLDL uptake was significantly decreased after AT treatment (P < 0.001). Cholesteryl ester accumulation was significantly decreased after AT enrichment (AcLDL + AT, 77% inhibition; OxLDL + AT, 42% inhibition). In conclusion, AT decreases both CD36 and SR-A expression and cholesteryl ester accumulation in human macrophages. This provides additional scientific support for the antiatherogenic properties of AT. —Devaraj, S., I. Hugou, and I. Jialal. α-Tocopherol decreases CD36 expression in human monocyte-derived macrophages. J. Lipid Res. 2001. 42: 521–527. Cholesterol-laden macrophages are the hallmark of atherogenesis. The class B scavenger receptor, CD36, binds oxidized low density lipoprotein (OxLDL), is found in atherosclerotic lesions, and is upregulated by OxLDL. We tested the effects of α-tocopherol (AT) enrichment of human monocyte-derived macrophages on CD36 expression and cholesteryl ester accumulation. Monocytes isolated from normal volunteers were cultured into macrophages. Macrophages were enriched overnight with various doses of AT (25, 50, and 100 μM). LDL from normal volunteers was oxidized or acetylated (AcLDL) and incubated with macrophages for 48 h at a concentration of 50 or 100 μg/ml. CD36 expression was assessed by flow cytometry. Quantitative analysis of scavenger receptor class A (SR-A) activity was performed with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanide perchlorate (DiI)-labeled LDL. CD36 expression was maximal after 8–10 days of culture. AT (≥50 μM) significantly decreased CD36 expression upregulated by OxLDL and AcLDL (P < 0.01). Other antioxidants (β- or γ-tocopherol) or protein kinase C inhibitors failed to decrease CD36 expression. Concomitantly, DiI-AcLDL and DiI-OxLDL uptake was significantly decreased after AT treatment (P < 0.001). Cholesteryl ester accumulation was significantly decreased after AT enrichment (AcLDL + AT, 77% inhibition; OxLDL + AT, 42% inhibition). In conclusion, AT decreases both CD36 and SR-A expression and cholesteryl ester accumulation in human macrophages. This provides additional scientific support for the antiatherogenic properties of AT. —Devaraj, S., I. Hugou, and I. Jialal. α-Tocopherol decreases CD36 expression in human monocyte-derived macrophages. J. Lipid Res. 2001. 42: 521–527. A number of epidemiological studies have demonstrated that increased levels of low density lipoproteins (LDL) are associated with an increased risk of atherosclerosis. However, the mechanism(s) by which LDL promotes the evolution of the fatty streak lesion remains to be elucidated. Uptake of cholesterol by the classic LDL receptor pathway cannot result in appreciable cholesterol accumulation because the LDL receptor is subject to feedback inhibition by the intracellular cholesterol content (1Brown M.S. Goldstein J.L. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis.Annu. Rev. Biochem. 1983; 52: 223-261Google Scholar). However, modified LDL, such as acetylated or oxidized LDL (AcLDL and OxLDL, respectively), can be taken up by the scavenger receptor (SR) pathway, resulting in unregulated cholesterol accumulation and foam cell formation. The most plausible and biologically relevant modification of LDL is oxidation (2Witztum J. Steinberg D. Role of oxidized low density lipoprotein in atherogenesis.J. Clin. Invest. 1991; 88: 1785-1792Google Scholar, 3Berliner J. Heinecke J. The role of oxidized lipoproteins in atherogenesis.Free Radic. Biol. Med. 1992; 92: 127-143Google Scholar, 4Devaraj S. Jialal I. Oxidized LDL and atherosclerosis.Int. J. Clin. Lab. Res. 1996; 26: 178-184Google Scholar, 5Berliner J.A. Navab M. Fogelman A.M. Frank J.S. Demer L.L. Edwards P.A. Watson A.D. Lusis A.J. Atherosclerosis: basic mechanisms, oxidation, inflammation and genetics.Circulation. 1995; 91: 2488-2496Google Scholar). Several lines of evidence point to a proatherogenic role for OxLDL. All major cells of the artery wall, such as monocyte-derived macrophages, endothelial cells, and smooth muscle cells, can oxidatively modify LDL in vitro (2Witztum J. Steinberg D. Role of oxidized low density lipoprotein in atherogenesis.J. Clin. Invest. 1991; 88: 1785-1792Google Scholar, 3Berliner J. Heinecke J. The role of oxidized lipoproteins in atherogenesis.Free Radic. Biol. Med. 1992; 92: 127-143Google Scholar, 4Devaraj S. Jialal I. Oxidized LDL and atherosclerosis.Int. J. Clin. Lab. Res. 1996; 26: 178-184Google Scholar, 5Berliner J.A. Navab M. Fogelman A.M. Frank J.S. Demer L.L. Edwards P.A. Watson A.D. Lusis A.J. Atherosclerosis: basic mechanisms, oxidation, inflammation and genetics.Circulation. 1995; 91: 2488-2496Google Scholar). Modified LDL, for example, OxLDL, is processed via the SR pathway. Because these receptors are not regulated by the intracellular cholesterol content, they can lead to substantial cholesteryl ester accumulation (6Goldstein J.L. Ho Y.K. Basu S.K. Brown M.S. Binding site on macrophages that mediates uptake and degradation of Ac-LDL producing massive cholesterol deposition.Proc. Natl. Acad. Sci.USA. 1979; 76: 333-337Google Scholar). The first SR was identified on macrophages as an AcLDL receptor, SR class A or SR-A (7Kodama T. Reddy P. Kishimoto C. Krieger M. Purification and characterization of a bovine acetyl low density lipoprotein receptor.Proc. Natl. Acad. Sci.USA. 1988; 85: 9238-9242Google Scholar). However acetylation does not occur under physiological circumstances. Other SR include MARCO, macrosialin, LOX-1, and SREC (8De Villiers W.J.S. Smart E.J. Macrophage scavenger receptors and foam cell formation.J. Leukoc. Biol. 1999; 66: 740-746Google Scholar). A second class of SR, SR class B (SR-B), has been identified as the OxLDL receptor. CD36, first cloned by Endemann et al. (9Endemann G. Stanton L.W. Madden K.S. Bryant C.M. White R.T. Protter A.A. CD36 is a receptor for OxLD.J. Biol. Chem. 1993; 268: 11811-11816Google Scholar), is a member of the SR-B family. It is an 88-kDa transmembrane glycoprotein expressed on monocyte-derived macrophages, platelets, adipocytes, and certain endothelial and epithelial cells (10Greenwalt D. Lipsky R. Ockenhouse C. Iheda H. Tandon N. Jamieson G. Membrane glycoprotein CD36: a review of its roles in adherance, signal transduction and transfusion medicine.Blood. 1992; 80: 1105-1115Google Scholar). CD36 may play a quantitatively significant role in modified LDL binding to macrophages (9Endemann G. Stanton L.W. Madden K.S. Bryant C.M. White R.T. Protter A.A. CD36 is a receptor for OxLD.J. Biol. Chem. 1993; 268: 11811-11816Google Scholar). In addition to binding AcLDL and OxLDL (11Calvo D. Gomez-Coronado D. Suarez M.A. Lasuncion A. Vega M.A. Human CD36 is a high affinity receptor for the native lipoproteins, HDL, LDL, VLDL.J. Lipid Res. 1998; 39: 777-788Google Scholar), CD36 binds thrombospondin (12Silverstein R.L. Baird M. Lo S.K. Yesner L.M. Role of CD36 as a thrombospondin receptor.J. Biol. Chem. 1992; 267: 16607-16612Google Scholar), anionic phospholipids (13Rigotti A. Acton S.L. Krieger M. The class B scavenger receptors SRB-1 and CD36 are receptors for anionic phospholipids.J. Biol. Chem. 1995; 270: 16221-16224Google Scholar), and long-chain fatty acids and collagen (14Tandon N.N. Kralisz U. Jamieson G.A. Identification of glycoprotein IV (CD36) as a primary receptor for plateletcollagen adhesion.J. Biol. Chem. 1989; 264: 7576-7583Google Scholar). CD36 is highly expressed on lipid-laden macrophages in human atherosclerotic aorta (15Nakata A. Nakagawa Y. Nishida M. Nozaki S. Miyagawa J. Nakagawa T. Tamura R. Matsumoto K. Kameda-Takemura K. Yamashita S. Matsuzawa Y. CD36 a novel receptor for OxLDL is highly expressed on lipid laden macrophages in human atherosclerotic lesions.Arterioscler. Thromb. Vasc. Biol. 1999; 19: 1333-1339Google Scholar). Monocyte-derived macrophages obtained from patients with inherited deficiency of CD36 bind 40% less OxLDL and accumulate 40% less cholesteryl ester compared with control cells. In addition, elicited macrophages derived from CD36 knockout mice bound and internalized 60% less modified LDL (16Nozaki S. Kashiwagi H. Yamashita S. Nakagawa T. Kostner B. Tomiyama Y. Nakata A. Ishigami M. Miyagawa J. Kameda-Takemura K. Kurata Y. Matsuzawa Y. Reduced uptake of OxLDL in monocyte derived macrophages from CD36 deficient subjects.J. Clin. Invest. 1995; 96: 1859-1865Google Scholar, 17Febbraio M. Abumrad N.A. Hajjar D.P. Sharma K. Cheng W. Pearce S.F.A. Silverstein R.L. A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism.J. Biol. Chem. 1999; 274: 19005-19062Google Scholar, 18Febbraio M. Podrez E.A. Smith J.D. Hajjar D.P. Hazen S.L. Hoff H.F. Sharma K. Silverstein R.L. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.J. Clin. Invest. 2000; 105: 1049-1056Google Scholar). CD36 and apolipoprotein E (apoE) double-knockout mice exhibit significantly less atherosclerosis than do apoE−/− mice (18Febbraio M. Podrez E.A. Smith J.D. Hajjar D.P. Hazen S.L. Hoff H.F. Sharma K. Silverstein R.L. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.J. Clin. Invest. 2000; 105: 1049-1056Google Scholar). CD36 has been shown to be upregulated by OxLDL in HL-60 and THP-1 cells via induction of the peroxisome proliferator-activated receptor γ (PPARγ) (19Nagy L. Tontonoz P. Alvarez J.G. Chen H. Evans R.M. OxLDL regulates macrophage gene expression through ligand activation of PPAR gamma.Cell. 1998; 93: 229-240Google Scholar) and in smooth muscle cells and RAW cells via protein kinase C (PKC) (20Feng J.W. Han J.H. Pearce S.F.A. Silverstein R.L. Gotto A.M. Hajjar D.P. Nicholson A.C. 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. 2000; 41: 688-696Google Scholar). These findings suggest that CD36 plays a key role in foam cell formation in atherosclerotic lesions and is therefore an important receptor to modulate. Also, it appears that the majority of modified LDL processing by macrophages is via CD36 and SR class A (SR-A) (40–90%) (16Nozaki S. Kashiwagi H. Yamashita S. Nakagawa T. Kostner B. Tomiyama Y. Nakata A. Ishigami M. Miyagawa J. Kameda-Takemura K. Kurata Y. Matsuzawa Y. Reduced uptake of OxLDL in monocyte derived macrophages from CD36 deficient subjects.J. Clin. Invest. 1995; 96: 1859-1865Google Scholar, 18Febbraio M. Podrez E.A. Smith J.D. Hajjar D.P. Hazen S.L. Hoff H.F. Sharma K. Silverstein R.L. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.J. Clin. Invest. 2000; 105: 1049-1056Google Scholar, 20Huh H.Y. Pearce Yesner L.M. J.L. Silverstein R.L. expression of CD36 1996; Scholar). α-Tocopherol (AT) is the most member of the E and is a R. and J. 1999; Scholar). are associated with increased risk of increased of AT to be In addition to the of LDL, AT has been shown to have antiatherogenic effects on endothelial cells, and smooth muscle cells A.C. E and 1998; Scholar). The monocyte-derived macrophage is a cell and is a cell that is in of atherogenesis. AT has been shown to cholesterol and uptake of AcLDL in cells, is a of the role of AT in CD36 expression and activity in human monocyte-derived macrophages, the cell in atherogenesis. the of was to the of AT on CD36 expression and in human monocyte-derived macrophages. cells were isolated from human volunteers by and were in of and as S. D. Jialal I. The effects of on monocyte lipid oxidation, and monocyte to Clin. Invest. 1996; Scholar). cells were in and incubated for h at cells were by the with and the cells were in the with human and The was The cells were after days of culture. by was in was in and macrophages were incubated in the of control or AT for h addition of modified LDL for 48 LDL was isolated from acid of volunteers by through and by through a and under in the at content was by the of et al. as S. D. Jialal I. The effects of on monocyte lipid oxidation, and monocyte to Clin. Invest. 1996; Scholar). LDL was with the 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanide perchlorate as by and Scholar) and acetylated to the of Basu et al. as I. A. in the metabolism of oxidatively modified low density lipoprotein and acetylated low density lipoprotein by human endothelial inhibition of cholesterol by oxidatively modified low density Lipid Res. 1989; Scholar). LDL was incubated overnight at with 50 of in for of LDL The LDL was by Scholar). The LDL be modification such as acetylation or OxLDL was by LDL with for h at as I. The of on LDL A Thromb. Vasc. Biol. 1995; Scholar). The of modification of LDL was by in an and by of at as I. The of on LDL A Thromb. Vasc. Biol. 1995; Scholar). We have the concentration in LDL, from as D. S. B. Jialal I. decreases the of LDL in patients on 2000; the concentration was a of an overnight with AT macrophages were incubated with DiI-AcLDL for 48 with cells were with and of was in Scholar). The of the was on with and at and were expressed as cells. In of after with cells were with and for uptake by flow cytometry. were with and with in The was incubated with for on The were and The cells were to the bound and with and were with The cells were on a as S. Jialal I. enrichment of decreases to human endothelial 1998; Scholar). with AcLDL or OxLDL in the or of AT or cells were with and and cholesterol levels were by after as I. A. in the metabolism of oxidatively modified low density lipoprotein and acetylated low density lipoprotein by human endothelial inhibition of cholesterol by oxidatively modified low density Lipid Res. 1989; Scholar). cholesterol levels were obtained by cholesterol from were in was with and in CD36 expression was performed with from with and for CD36 for at at as that were to CD36 and as H. N. S. Steinberg D. expression of CD36 and in Thromb. Vasc. Biol. 1998; Scholar). The were by on and the signal of the with the was were to significant in in the and of AT and the of was at < All have been performed at of human monocyte-derived macrophages overnight with 50, and 100 AT, was a enrichment of macrophages with AT and CD36 expression was dependent and was maximal at days of AT enrichment in significant inhibition of CD36 expression on days and All were after days in culture. In to AT, with or resulting in a and enrichment in macrophages compared with not significantly CD36 expression and decrease compared with and with AT (≥50 μM) significantly decreased macrophage CD36 expression after with AcLDL and with AT at 50 and 100 and OxLDL and 77% with AT at 50 and 100 and Also, of macrophages with the to CD36 its expression by both AcLDL and OxLDL DiI-AcLDL and DiI-OxLDL uptake was to the of AT on SR-A DiI-AcLDL uptake was significantly after with and < 0.01). AT significantly DiI-AcLDL as as DiI-OxLDL uptake by and the of and AT was with to inhibition of DiI-AcLDL and DiI-OxLDL uptake AcLDL + 50 AcLDL + AcLDL + AT + OxLDL + OxLDL + OxLDL + AT + were obtained with acid of macrophages with AcLDL or OxLDL significantly cholesteryl ester accumulation in macrophages compared with control is in after AT was a significant decrease in cholesteryl ester accumulation in macrophages compared with AcLDL < or OxLDL < CD36 expression was upregulated in the of AcLDL or OxLDL. However, of macrophages with AT on CD36 in control cells or in or cells was significant in in the and of AT. by which AT decreased CD36 the of inhibitors on CD36 expression was by flow because AT has been shown to C and and and μM) not result in significant in CD36 expression not levels of AT have been associated with increased of artery and and of AT are associated with decreased of H. N. S. Steinberg D. expression of CD36 and in Thromb. Vasc. Biol. 1998; Scholar, P. P. U. E and from in J. Clin. 1992; Scholar, of and of and E and 1991; Scholar, A. G.A. E and the risk of in J. Med. 1993; Scholar). modification of LDL is to be an important in (2Witztum J. Steinberg D. Role of oxidized low density lipoprotein in atherogenesis.J. Clin. Invest. 1991; 88: 1785-1792Google Scholar, 3Berliner J. Heinecke J. The role of oxidized lipoproteins in atherogenesis.Free Radic. Biol. Med. 1992; 92: 127-143Google Scholar, 4Devaraj S. Jialal I. Oxidized LDL and atherosclerosis.Int. J. Clin. Lab. Res. 1996; 26: 178-184Google Scholar, 5Berliner J.A. Navab M. Fogelman A.M. Frank J.S. Demer L.L. Edwards P.A. Watson A.D. Lusis A.J. Atherosclerosis: basic mechanisms, oxidation, inflammation and genetics.Circulation. 1995; 91: 2488-2496Google Scholar), and studies have on the of AT, that the of LDL to oxidation R. and J. 1999; Scholar, G.A. B. E and the risk of in J. Med. 1993; Scholar, H. M. G. G. Role of E in the oxidation of J. Clin. 1991; Scholar, G. C. R. with E not in protects low density lipoprotein from lipid in of Thromb. 1992; Scholar, S. B. Jialal I. of and on LDL Thromb. Vasc. Biol. Scholar). Also, evidence of the antiatherogenic effects of AT on cells in such as endothelial cells, platelets, smooth muscle cells, and monocyte-derived macrophages is R. and J. 1999; Scholar, A.C. E and 1998; Scholar). The monocyte-derived macrophage is a cell in the and is of atherogenesis. The formation of foam cells in the the fatty streak is an important in R. J. Med. 1999; Scholar). We have shown that AT significantly decreased monocyte proatherogenic activity lipid of such as and and to and decreased levels of in human volunteers as as in are to atherosclerosis S. D. Jialal I. The effects of on monocyte lipid oxidation, and monocyte to Clin. Invest. 1996; Scholar, S. Jialal I. lipoprotein monocyte and in patients with and the of 2000; Scholar). studies at that AT decreased monocyte and lipid oxidation via inhibition of activity S. D. Jialal I. The effects of on monocyte lipid oxidation, and monocyte to Clin. Invest. 1996; Scholar), the of from human via inhibition of S. Jialal I. decreases from human by inhibition of Thromb. Vasc. Biol. 1999; 19: Scholar), decreased cell via inhibition of and decreased expression of and on S. Jialal I. enrichment of decreases to human endothelial 1998; Scholar). In addition to these intracellular that in human monocyte-derived macrophages, AT novel effects of CD36 SR expression and cholesteryl ester and foam cell a hallmark of the atherosclerotic CD36 is the major receptor for the uptake of modified LDL. Human macrophage CD36 expression is upregulated by and is in 8–10 days of culture. Nakagawa et al. T. Nozaki S. Nishida M. Tomiyama Y. Nakata A. Matsumoto K. T. Kameda-Takemura K. Kurata Y. Yamashita S. Matsuzawa Y. OxLDL and decreases expression of CD36 in human monocyte-derived Thromb. Vasc. Biol. 1998; Scholar) that in human macrophages, CD36 expression was maximal after days of culture. This is in to et al. H.Y. Pearce Yesner L.M. J.L. Silverstein R.L. expression of CD36 1996; Scholar), have shown that CD36 expression is upregulated and is maximal on to and is by of culture. This may be because were cultured in from in for macrophages in of macrophages with AcLDL or OxLDL significantly CD36 expression This is in with Han et al. J. Hajjar D.P. M. Nicholson A.C. and modified LDL expression of macrophage Biol. Chem. 1996; Scholar, J. Hajjar D.P. Nicholson A.C. cholesterol regulates expression of the macrophage B scavenger receptor, Lipid Res. 1999; Scholar), have shown that modified LDL and cholesterol CD36 expression in murine macrophages. of macrophages with AT at doses that can be with significantly decreased CD36 expression in human monocyte-derived macrophages. the inhibition by AT was to its macrophages were incubated with or which have and in the of the on the CD36 expression in human monocyte-derived macrophages was not by these and D. J. D. scavenger receptor activity in 1999; Scholar) have shown that and not or SR-A activity in macrophages and α-tocopherol However, they not on CD36 expression or cholesteryl ester accumulation. was in and R. A. E the uptake of oxidized LDL by CD36 scavenger receptor expression in cultured smooth muscle 2000; Scholar) that not CD36 expression in a cultured human smooth muscle cell by CD36 and protein expression. However, they not the of AT on SR-A activity or intracellular cholesteryl ester accumulation. they not the of AT on CD36 expression in human monocyte-derived macrophages, the cells in and not the of AT on CD36 in HL-60 cells. Also, the of AT on CD36 expression upregulated by modified LDL was not AT decreased CD36 expression or effects on SR-A activity as analysis of SR activity was performed with AcLDL and OxLDL. DiI-AcLDL uptake was significantly after with or AT significantly DiI-AcLDL as as DiI-OxLDL uptake by human macrophages. the of and AT was with to inhibition of DiI-AcLDL it appears that AT effects in SR-A and CD36 and R. A. E the uptake of oxidized LDL by CD36 scavenger receptor expression in cultured smooth muscle 2000; Scholar) demonstrated decreased uptake of by the human smooth muscle cell they failed to intracellular cholesteryl ester accumulation. decreased expression of CD36 to decreased cholesteryl ester cholesteryl ester accumulation in macrophages was with AcLDL or OxLDL significantly increased cholesteryl ester accumulation. AT significantly cholesteryl ester accumulation after with AcLDL and OxLDL. et al. M. M. P. of with E on uptake of LDL and of cholesterol ester formation in Scholar) that enrichment of a murine macrophage cell with AT LDL oxidation and cholesteryl ester formation. However, they not these effects of AT were to the decreased of macrophages to LDL or to its effects on cholesterol et al. R. of cholesteryl ester accumulation in cells by increased E on of J. Biochem. 1995; Scholar) that enrichment of murine macrophages with AT the of cholesteryl ester to cholesterol after with bovine not modified LDL. et al. H. T. M. M. Yamashita T. E cholesterol and uptake of Ac-LDL in 1998; Scholar) that AT μM) significantly uptake of AcLDL with a of resulting in decreased cholesteryl in cells, a murine macrophage cell However, they not the of AT on cholesteryl ester accumulation. The in that in human monocyte-derived macrophages, AT decreases CD36 expression and SR and is associated with decreased cholesteryl ester accumulation. the in CD36 expression and activity in human monocyte-derived macrophages by AT was to decreased for CD36 expression was upregulated in the of both AcLDL and OxLDL as AT enrichment not have on CD36 In a cell of smooth muscle cells, AT appears to CD36 R. A. E the uptake of oxidized LDL by CD36 scavenger receptor expression in cultured smooth muscle 2000; Scholar). However, the in cell in studies may in in human monocyte-derived macrophages, AT appears to CD36 expression at the et al. (20Feng J.W. Han J.H. Pearce S.F.A. Silverstein R.L. Gotto A.M. Hajjar D.P. Nicholson A.C. 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. 2000; 41: 688-696Google Scholar) have shown that induction of CD36 expression by OxLDL in a murine macrophage cell RAW activation of AT has been shown to decrease activity in S. D. Jialal I. The effects of on monocyte lipid oxidation, and monocyte to Clin. Invest. 1996; Scholar). tested the of inhibitors on CD36 expression by flow cytometry. In with human monocyte-derived macrophages, inhibitors failed to significantly CD36 expression. AT decreases smooth muscle cell and monocyte and lipid oxidation via inhibition of R. and J. 1999; Scholar, A.C. E and 1998; Scholar), in cell muscle cells and human CD36 expression is not regulated by AT via inhibition of R. A. E the uptake of oxidized LDL by CD36 scavenger receptor expression in cultured smooth muscle 2000; Scholar). It is that AT which has been in CD36 by OxLDL (19Nagy L. Tontonoz P. Alvarez J.G. Chen H. Evans R.M. OxLDL regulates macrophage gene expression through ligand activation of PPAR gamma.Cell. 1998; 93: 229-240Google Scholar, J.W. Han J.H. Pearce S.F.A. Silverstein R.L. Gotto A.M. Hajjar D.P. Nicholson A.C. 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. 2000; 41: 688-696Google Scholar) in macrophages. A decrease in the pathway does not to be the because a PPAR that a E and does not decrease CD36 expression. Han et al. J. Hajjar D.P. J. Gotto A.M. Nicholson A.C. and decrease expression of CD36, the B scavenger receptor, through protein kinase of peroxisome proliferator-activated Biol. Chem. 2000; Scholar) that and decreased CD36 expression and in THP-1 cells. Because failed to an on CD36 in human monocyte-derived macrophages, is to the inhibition of CD36 expression and cholesteryl ester accumulation by AT. studies be at the by which AT decreases CD36 such as its on kinase activity and which to CD36 expression. In for the first in human monocyte-derived macrophages that AT enrichment in decreased CD36 decreased SR and decreased cholesteryl ester and that the of inhibition appears to be These with effects of AT decrease in LDL oxidation, in endothelial decrease in monocyte and smooth muscle cell support for the antiatherogenic effects of AT. This was by from the of and the