2002/01/01 by John M. Hayden, Libuse Brachova, Karen M. Higgins +5 · 9 citations
Medicine · Immunology and Microbiology · #Cholesterol and Lipid Metabolism #Atherosclerosis and Cardiovascular Diseases #Immune Cell Function and Interaction
paper · doi:10.1016/s0022-2275(20)30183-8
Oxidized LDL (OxLDL) is composed of many potentially proatherogenic molecules, including oxysterols. Of the oxysterols, 7-ketocholesterol (7-KC) is found in relatively large abundance in OxLDL, as well as in atherosclerotic plaque and foam cells in vivo. Although there is evidence that 7-KC activates endothelial cells, its effect on monocytes is unknown. We tested the hypothesis that 7-KC may induce monocyte differentiation and promote foam cell formation. THP-1 cells were used as a monocyte model system and were treated with 7-KC over a range of concentrations from 0.5 to 10 μg/ml. Changes in cell adhesion properties, cell morphology, and expression of antigens characteristic of differentiated macrophages were monitored over a 7-day period. 7-KC promoted cells to firmly adhere and display morphologic features of differentiated macrophages; this effect was time and dose dependent and was markedly more potent than cholesterol treatment (45% of cells became adherent after 7 days of treatment with 7-KC at 10 μg/ml vs. less then 5% for control cells, P < 0.01). Similar effects were obtained when LDL enriched with 7-KC or OxLDL were added to THP-1 cells. 7-KC-differentiated cells expressed CD11b, CD36, and CD68, phagocytized latex beads, and formed lipid-laden foam cells after exposure to acetylated LDL or OxLDL. In contrast to 7-KC, oxysterols with known cell regulatory effects such as 25-hydroxycholesterol, 7β-hydroxycholesterol, and (22R)-hydroxycholesterol did not effectively promote THP-1 differentiation. In conclusion, these results demonstrate for the first time that 7-KC, a prominent oxysterol formed in OxLDL by peroxidation of cholesterol, may play an important role in promoting monocyte differentiation and foam cell formation. These studies also suggest that 7-KC induces monocyte differentiation through a sterol-mediated regulatory pathway that remains to be characterized. —Hayden, J. M., L. Brachova, K. Higgins, L. Obermiller, A. Sevanian, S. Khandrika, and P. D. Reaven. Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol. J. Lipid Res. 2002. 43: 26–35. Oxidized LDL (OxLDL) is composed of many potentially proatherogenic molecules, including oxysterols. Of the oxysterols, 7-ketocholesterol (7-KC) is found in relatively large abundance in OxLDL, as well as in atherosclerotic plaque and foam cells in vivo. Although there is evidence that 7-KC activates endothelial cells, its effect on monocytes is unknown. We tested the hypothesis that 7-KC may induce monocyte differentiation and promote foam cell formation. THP-1 cells were used as a monocyte model system and were treated with 7-KC over a range of concentrations from 0.5 to 10 μg/ml. Changes in cell adhesion properties, cell morphology, and expression of antigens characteristic of differentiated macrophages were monitored over a 7-day period. 7-KC promoted cells to firmly adhere and display morphologic features of differentiated macrophages; this effect was time and dose dependent and was markedly more potent than cholesterol treatment (45% of cells became adherent after 7 days of treatment with 7-KC at 10 μg/ml vs. less then 5% for control cells, P < 0.01). Similar effects were obtained when LDL enriched with 7-KC or OxLDL were added to THP-1 cells. 7-KC-differentiated cells expressed CD11b, CD36, and CD68, phagocytized latex beads, and formed lipid-laden foam cells after exposure to acetylated LDL or OxLDL. In contrast to 7-KC, oxysterols with known cell regulatory effects such as 25-hydroxycholesterol, 7β-hydroxycholesterol, and (22R)-hydroxycholesterol did not effectively promote THP-1 differentiation. In conclusion, these results demonstrate for the first time that 7-KC, a prominent oxysterol formed in OxLDL by peroxidation of cholesterol, may play an important role in promoting monocyte differentiation and foam cell formation. These studies also suggest that 7-KC induces monocyte differentiation through a sterol-mediated regulatory pathway that remains to be characterized. —Hayden, J. M., L. Brachova, K. Higgins, L. Obermiller, A. Sevanian, S. Khandrika, and P. D. Reaven. Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol. J. Lipid Res. 2002. 43: 26–35. It is now widely recognized that monocytes play an integral role in the development and progression of atherosclerosis (1Ross R. Atherosclerosis is an inflammatory disease.Am. Heart J. 1999; 138: S419-S420Google Scholar, 2Navab M. Berliner J.A. Watson A.D. Hama S.Y. Territo M.C. Lusis A.J. Shih D.M. Van Lenten B.J. Frank J.S. Demer L.L. Edwards P.A. Fogelman A.M. The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 831-842Google Scholar). Monocytes are among the first cells present in lesion-prone areas, and they continue to accumulate during plaque formation. On exposure to a variety of regulatory signals, monocytes rapidly differentiate into tissue macrophages in the vascular intima. When activated, monocyte-macrophages may secrete multiple cytokines and free radicals that promote inflammation and atherosclerosis (1Ross R. Atherosclerosis is an inflammatory disease.Am. Heart J. 1999; 138: S419-S420Google Scholar, 3Henson P.M. Riches D.W. Modulation of macrophage maturation by cytokines and lipid mediators: a potential role in resolution of pulmonary inflammation.Ann. N.Y. Acad. Sci. 1994; 725: 298-308Google Scholar, 4Liu Y. Hulten L.M. Wiklund O. Macrophages isolated from human atherosclerotic plaques produce IL-8, and oxysterols may have a regulatory function for IL-8 production.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 317-323Google Scholar). Macrophages also express multiple scavenger receptors that facilitate internalization of modified lipoproteins, leading to the development of cholesterol-laden foam cells and plaque formation in arteries (5Edwards P.A. Ericsson J. Signaling molecules derived from the cholesterol biosynthetic pathway: mechanisms of action and possible roles in human disease.Curr. Opin. Lipidol. 1998; 9: 433-440Google Scholar, 6Yamada Y. Doi T. Hamakubo T. Kodama T. Scavenger receptor family proteins: roles for atherosclerosis, host defence and disorders of the central nervous system.Cell. Mol. Life Sci. 1998; 54: 628-640Google Scholar, 7Steinbrecher U.P. Receptors for oxidized low density lipoprotein.Biochim. Biophys. Acta. 1999; 1436: 279-298Google Scholar). The primary role of monocyte-macrophages in atherogenesis has been confirmed in gene knockout mice lacking monocyte chemoattractant protein or its receptor, CCR2. In these respective mouse models it was demonstrated that aortic atherosclerosis was significantly reduced in comparison with wild-type controls under experimental conditions that predispose to atherosclerosis (8Gosling J. Slaymaker S. Gu L. Tseng S. Zlot C.H. Young S.G. Rollins B.J. Charo I.F. MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B.J. Clin. Invest. 1999; 103: 773-778Google Scholar, 9Boring L. Gosling J. Cleary M. Charo I.F. Decreased lesion formation in CCR2−;/− mice reveals a role for chemokines in the initiation of atherosclerosis.Nature. 1998; 394: 894-897Google Scholar). Although the consequences of macrophage accumulation in lesion-susceptible regions of the artery wall are now evident, the regulatory signals that induce monocyte differentiation in this environment are less completely understood. Although it has been demonstrated that oxidized low density lipoprotein (OxLDL) can induce the differentiation of monocytes (10Frostegard J. Nilsson J. Haegerstrand A. Hamsten A. Wigzell H. Gidlund M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937.Proc. Natl. Acad. Sci. USA. 1990; 87: 904-908Google Scholar), the components of OxLDL that actually promote this process are not fully elucidated. Initial studies have suggested that oxidized phospholipids are remarkably proinflammatory, and at least one report has implicated specific oxidized phospholipids in the regulation of monocyte differentiation (11Rajavashisth T.B. Andalibi A. Territo M.C. Berliner J.A. Navab M. Fogelman A.M. Lusis A.J. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins.Nature. 1990; 344: 254-257Google Scholar). Other components of OxLDL, such as oxysterols, have also been shown to promote a variety of potentially proatherogenic events. Of the oxysterols, 7-ketocholesterol (7-KC) has been found in relatively high concentrations in OxLDL produced in vitro (12Brown A.J. and its in oxidized low density lipoprotein and human atherosclerotic Lipid Res. 1997; Scholar, A. of cholesterol oxidation formed by of low density Biol. 1997; Scholar, S. of oxysterols during oxidation of low density lipoprotein by and Lipid Res. 1996; and is enriched in foam cells and atherosclerotic plaque in L.M. H. M. Y. Wiklund O. present in atherosclerotic tissue the expression of lipoprotein in human Clin. Invest. 1996; Scholar, A.J. and 1999; Scholar). 7-KC induces in vascular cells M. S. P. L. Induction of features of in human and vascular endothelial cells treated by 1997; Scholar, Y. K. Y. J. Y. T. H. of oxysterols on human vascular cells was by Thromb. 1997; Scholar), adhesion expression in endothelial cells S. S. S. P. D. of adhesion expression and in human endothelial cells treated with or 1998; Scholar), and cholesterol in macrophages A.J. L. is from macrophage foam cells enriched with Biol. 1996; Scholar). the effects of oxysterols on differentiation have not been demonstrate for the first time that 7-KC differentiation of THP-1 cells and primary human and foam cell formation in THP-1 cells were in 10 and at in 5% In cells were at a density of Initial demonstrated that THP-1 cells were more to differentiation after with in in this THP-1 cells were treated with for exposure to oxysterols. with was added to a of in the and oxysterols were added to 10 to the cells for to 7 of oxysterols and were in The of were with at a the 7-KC used in the concentrations were in this did not of differentiation that was in the or cholesterol in as controls in In was added to THP-1 cells to as a control for differentiation. In confirmed that oxysterol of THP-1 cells did not from potential in 7-KC or cell human monocytes were isolated from that was obtained from The was with and on and at for at The was with and in that was with the cells were by with and the adherent cells were for Monocytes were then to or to 7-KC and for 7 days conditions THP-1 cells in after treatment with 7-KC a of cells adherent to 7 this morphologic of the adherent cells were by or In adherent cells were from the by treatment with and with a or a In cell was also by the of protein cells and THP-1 cells that in after 7-KC exposure were to by at for at that were to the and cells that were to adhere to by 7-KC, were by in for 10 at the cells were with and was by with in for The cells were then with mouse or for with primary and CD68, and and CD36, for at primary were by with a by treatment as the of of primary cells were treated with a or with primary adherent THP-1 cells demonstrate the of latex in were added to cells for at and 5% The cells were then with and latex were by the potential effect of 7-KC on THP-1 cells, in the was from cells and adherent cells treated to 7 days with The of was as the of in the by from from the cell In was used to the of and adherent THP-1 cells after exposure to cells and were as LDL was isolated from by by as B.J. of and in with on the susceptibility of LDL and LDL to in Thromb. 1994; Scholar). or LDL were also from that was first at for with a of 7-KC of or as used for A.J. L. is from macrophage foam cells enriched with Biol. 1996; Scholar). The of 7-KC in LDL was by as A. of cholesterol oxidation formed by of low density Biol. 1997; Scholar). LDL were and in the at LDL was LDL was by the of to LDL on macrophages that and of acetylated low density cholesterol Natl. Acad. Sci. USA. and OxLDL was by treatment with at for as B.J. of and in with on the susceptibility of LDL and LDL to in Thromb. 1994; Scholar). The of LDL oxidation was by formation K. A for in Scholar). In oxidation and of LDL were also confirmed by comparison with LDL by In these LDL were by with THP-1 cells 7 days of 7-KC treatment at were treated with and in at a density of for The cells were then with of protein with or or LDL of protein for at and 5% The cells were then with and was at and with a at The specific from treatment was by obtained from THP-1 cells. the effect of 7-KC exposure on foam cell THP-1 cells were treated with 7-KC for 7 this the cells were and the adherent cells were and was with or OxLDL of protein for The cells were then with with and with were then by cell were 7 days after treatment with 7-KC, or as The cells were in and The protein of was by the at to were by to and to by with of a and The were with a 10 and 5% for at least the of the primary range from to for or the primary were and were added in a range of to for at were by and by exposure to for of the protein was then by THP-1 and primary monocytes were treated with 7-KC and for 7 days as was from the cells by the and the was with and in The of was then by at at The effect of 7-KC on CD68, CD36, and macrophage scavenger receptor abundance was by this system and of in a by a that a system for of and to was added in the system with and for of the CD68, and CD36, and and and of were also and as an control S. of in human 1997; 138: Scholar). was formed at for and the of an for by of for for and for and for and for 7 was by in and with of was to < treatment and time effects of treatment were by the vs. and as Initial studies the effect of 7-KC on THP-1 cell differentiation demonstrated that these cells, in to in of 7 to cells after of 7-KC of exposure to this oxysterol a of the cells to 7 days of the adherent THP-1 cells in the and formed of macrophages THP-1 cells treated with and cells treated with cholesterol not did not these We also the adherent THP-1 cells from exposure to 7-KC 0.5 to 10 for 7 The and of adherent cells in to and time of exposure to 7-KC P < P < 7-KC at 10 μg/ml of the cell to adherent more the effects of low of 7-KC on THP-1 cell protein in cell from well was The results from this that protein of also after 7-KC treatment in a < not In a cell and protein of adherent cells P < was present in these that the in adherent cell protein was not to an in actually from an in cell On the of these the of adherent cell protein was used in the of to effects of 7-KC treatment on cell Similar were with LDL that was isolated from to or 7-KC LDL 7-KC and LDL with 7-KC 7-KC were added to THP-1 cells in a that and of LDL protein for 7 LDL effect on THP-1 cell LDL that was enriched with 7-KC in cell and that are characteristic of differentiation. These effects in a not and cell for the LDL treatment at of protein In the effect on cell produced by LDL by 7-KC that was in In OxLDL to also cell this effect less than that of 7-KC treatment the effect of LDL on THP-1 cell days and a time that is to of monocyte differentiation by OxLDL or 7-KC in have shown that oxysterols may produce in cell the dose range of 7-KC used in the present may induce THP-1 cell the of in THP-1 cells in after 7-KC treatment demonstrated that concentrations of 7-KC from 0.5 to μg/ml did not induce cell when with control cells. In exposure of THP-1 cells to 7-KC at 10 μg/ml for 7 days significantly the of cells cells vs. for P < In contrast to the THP-1 cells in adherent cells did not for when this of cells was to of 7-KC to μg/ml. The of from THP-1 cells to 7-KC a as the 10 μg/ml dose of 7-KC significantly and of in the of THP-1 cells after 7 days of treatment in vs. P < 0.01). In in a of was not by 7-KC treatment to in the adherent of THP-1 cells. On the of these the of 7-KC used in cell did not μg/ml. 7-KC THP-1 cell THP-1 cells that became adherent to this treatment were for the expression of protein CD36, and that The of adherent cells demonstrated high of and expression and of the cells expressed In control cells to a and cells that were treated with cholesterol not did not demonstrate expression of these We also studies to 7-KC also facilitate differentiation of human with THP-1 cells, human monocytes treated with 7-KC to morphologic characteristic of differentiation to macrophages at an as with cells not in comparison with monocytes cells treated for with 7-KC at μg/ml demonstrated expression of and expression of the macrophage were on THP-1 cells treated with In these to the scavenger receptors and of role in oxidized lipoprotein and foam cell shown in 7-KC abundance in differentiated THP-1 cells < for μg/ml and P < for μg/ml vs. protein expression was also significantly by 7-KC treatment μg/ml vs. P < was to 7-KC treatment the expression of CD68, CD36, and Similar to the of for and were by 7-KC In there was a in the of that this of scavenger receptor may also be by 7-KC the scavenger the expression of was not by 7-KC These results that 7-KC treatment the expression of a variety of scavenger and suggest that regulation by this oxysterol may in at the of that differentiated cells demonstrate of these cells can modified and lipid-laden foam cells. demonstrated in 7-KC-differentiated cells demonstrated a to multiple latex These also evidence that exposure to 7-KC not the of differentiated THP-1 cells. is a for multiple scavenger receptors including CD36, and demonstrate the of 7-KC-differentiated cells to and modified adherent cells with or of protein for at In of protein or of protein were added as for and In the of or was significantly than P < In not effectively reduced the of in a of the THP-1 macrophages in and were to of differentiated cells with promote development of lipid-laden foam cells. The of at of protein to these cells for to lipid internalization and foam cell development effect was also by the of OxLDL at the for has demonstrated that oxysterols, for may important (5Edwards P.A. Ericsson J. Signaling molecules derived from the cholesterol biosynthetic pathway: mechanisms of action and possible roles in human disease.Curr. Opin. Lipidol. 1998; 9: 433-440Google Scholar, S. and evidence for gene regulation the cholesterol Mol. Biol. 1999; Scholar). of oxysterols may also induce THP-1 differentiation. A of oxysterols, including 7β-hydroxycholesterol, and 25-hydroxycholesterol, was added to THP-1 cells over the range of concentrations to that was for shown in 7-KC the to induce THP-1 cell and this effect in a with and THP-1 cell 7 days of concentrations of and markedly cell and did not monocyte differentiation. In contrast to the oxysterols, did not effect THP-1 differentiation when at concentrations of the oxysterol were also and these did not induce THP-1 cell differentiation not The factors that to the of monocytes to macrophages in the artery wall are not well understood. studies have that OxLDL may play a role in promoting differentiation of monocytes to macrophages (10Frostegard J. Nilsson J. Haegerstrand A. Hamsten A. Wigzell H. Gidlund M. Oxidized low density lipoprotein induces differentiation and adhesion of human monocytes and the monocytic cell line U937.Proc. Natl. Acad. Sci. USA. 1990; 87: 904-908Google Scholar, T.B. Andalibi A. Territo M.C. Berliner J.A. Navab M. Fogelman A.M. Lusis A.J. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins.Nature. 1990; 344: 254-257Google Scholar). It has been demonstrated that oxidized phospholipids from LDL are and may be for of the effects of through of vascular wall cells M. Berliner J.A. Watson A.D. Hama S.Y. Territo M.C. Lusis A.J. Shih D.M. Van Lenten B.J. Frank J.S. Demer L.L. Edwards P.A. Fogelman A.M. The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 831-842Google Scholar). such is the by of macrophage colony-stimulating from endothelial cells (11Rajavashisth T.B. Andalibi A. Territo M.C. Berliner J.A. Navab M. Fogelman A.M. Lusis A.J. Induction of endothelial cell expression of granulocyte and macrophage colony-stimulating factors by modified low-density lipoproteins.Nature. 1990; 344: 254-257Google Scholar). is a for the and differentiation of cells into and may promote differentiation of monocytes S. S. monocyte and differentiation into macrophages in Scholar). The consequences of formation are to be in lesion formation. atherosclerotic more leading to more oxidation of and cell and of oxysterols, such as 7-KC A. of cholesterol oxidation formed by of low density Biol. 1997; Scholar, S. of oxysterols during oxidation of low density lipoprotein by and Lipid Res. 1996; Scholar, A.J. and formation during of low density lipoprotein and by Lipid Res. 1996; Scholar). these of cholesterol oxidation are found in concentrations in foam cells and in L.M. H. M. Y. Wiklund O. present in atherosclerotic tissue the expression of lipoprotein in human Clin. Invest. 1996; Scholar, A.J. and 1999; Scholar). In this demonstrate that 7-KC can promote differentiation of THP-1 cells, a monocytic cell line S. M. Y. Y. T. K. and of a human monocytic cell line J. Scholar, J. The human cell a model for the of Scholar). THP-1 cells treated with 7-KC demonstrated to tissue and morphologic and expression of that are characteristic of Similar to the time of human monocyte differentiation in this process to 7 days for THP-1 macrophages to cells treated with LDL were also to adhere and the morphologic of differentiation. these LDL were not oxidized and were enriched in 7-KC, these demonstrate that 7-KC, free in or lipoproteins, is a potent of monocyte differentiation. THP-1 cells to OxLDL also differentiated over the time as cells to Although many are formed during LDL it has been demonstrated that a oxysterol from is 7-KC (12Brown A.J. and its in oxidized low density lipoprotein and human atherosclerotic Lipid Res. 1997; Scholar, A. of cholesterol oxidation formed by of low density Biol. 1997; Scholar, S. of oxysterols during oxidation of low density lipoprotein by and Lipid Res. 1996; Scholar). these studies suggest that 7-KC may be one of the components this of LDL that induces monocyte differentiation. THP-1 cells to adhere to tissue after treatment with 7-KC the of macrophage cells. demonstrated and were to modified through scavenger receptors in an leading to foam cell formation in monocytes treated with 7-KC also to morphologic characteristic of differentiation at an as with cells. also that 7-KC can promote scavenger receptor expression in these human These suggest that the effect of 7-KC is not to the THP-1 cell The by 7-KC induces macrophage differentiation is may that 7-KC may induce of cytokines that monocyte differentiation. The relatively of cell and morphologic in cells is with this hypothesis and is in contrast to the effects produced by the protein It has also been demonstrated that OxLDL and oxysterols, including 7-KC, are of cytokines in vascular cells M. Berliner J.A. Watson A.D. Hama S.Y. Territo M.C. Lusis A.J. Shih D.M. Van Lenten B.J. Frank J.S. Demer L.L. Edwards P.A. Fogelman A.M. The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture.Arterioscler. Thromb. Vasc. Biol. 1996; 16: 831-842Google Scholar, 4Liu Y. Hulten L.M. Wiklund O. Macrophages isolated from human atherosclerotic plaques produce IL-8, and oxysterols may have a regulatory function for IL-8 production.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 317-323Google Scholar, S. S. S. P. D. of adhesion expression and in human endothelial cells treated with or 1998; Scholar). In studies have shown that 7-KC the of and in THP-1 cells not these cytokines are potent of differentiation and of cell and may to the differentiation of 7-KC may also have a regulatory effect on THP-1 cell differentiation. have been shown to have a of effects on gene regulation (5Edwards P.A. Ericsson J. Signaling molecules derived from the cholesterol biosynthetic pathway: mechanisms of action and possible roles in human disease.Curr. Opin. Lipidol. 1998; 9: 433-440Google Scholar, oxysterol pathway by the receptor 1996; Scholar, P.M. of the receptor by Natl. Acad. Sci. USA. 1997; Scholar). and are receptors to that and 25-hydroxycholesterol, and facilitate regulation of cell lipid oxysterol pathway by the receptor 1996; Scholar, P.M. of the receptor by Natl. Acad. Sci. USA. 1997; Scholar). Of and 25-hydroxycholesterol, with of oxysterols and cholesterol, were relatively in THP-1 that 7-KC may through a studies in are on of potential mechanisms of 7-KC that oxysterols may to atherosclerosis has over of oxysterols in with atherosclerotic than in controls L. of oxysterols in the is to endothelial Scholar). of 7-KC are in L.M. H. M. Y. Wiklund O. present in atherosclerotic tissue the expression of lipoprotein in human Clin. Invest. 1996; Scholar), and these are to used in in the present A in the has also been the of of oxysterols, including 7-KC, in foam cells and atherosclerotic plaque Y. Hulten L.M. Wiklund O. Macrophages isolated from human atherosclerotic plaques produce IL-8, and oxysterols may have a regulatory function for IL-8 production.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 317-323Google Scholar, L.M. H. M. Y. Wiklund O. present in atherosclerotic tissue the expression of lipoprotein in human Clin. Invest. 1996; Scholar, A.J. and 1999; Scholar). of oxysterols in these are than in the that oxysterol may in the atherosclerotic the evidence a role for oxysterols in atherosclerotic has been that or with oxysterols have atherosclerosis than control A.J. and 1999; Scholar, Oxidized cholesterol in the the development of aortic atherosclerosis in Thromb. Vasc. Biol. 1998; Scholar, Oxidized cholesterol in the the development of atherosclerosis in LDL and apolipoprotein Thromb. Vasc. Biol. Scholar, L. A. A. oxidation induce vascular foam cell lesion formation in Thromb. Vasc. Biol. 1999; Scholar). the that oxidation of may to atherosclerosis has there has been in the role of components of OxLDL in these events. more oxidation of as in more or foam cells, accumulation of 7-KC is present S. of oxysterols during oxidation of low density lipoprotein by and Lipid Res. 1996; Scholar, A.J. and formation during of low density lipoprotein and by Lipid Res. 1996; Scholar). oxysterol has been shown to be and is The that 7-KC may also monocyte differentiation and foam cell formation. OxLDL one or more oxysterol to have the to the and of macrophages J.A. D. R. S. Oxidized LDL can induce macrophage and to and Thromb. Vasc. Biol. 1999; Scholar). of and of macrophages to that are enriched with oxysterols may to progression of of the mechanisms that these may for of was by from the and the The of are