FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2122238876> ?p ?o ?g. }

• W2122238876 endingPage "6935" @default.
• W2122238876 startingPage "6927" @default.
• W2122238876 abstract "Oxidation of low density lipoprotein (LDL) results in changes to the lipoprotein that are potentially atherogenic. Numerous studies have shown that macrophages cultured in vitro can promote LDL oxidation via a transition metal-dependent process, yet the exact mechanisms that are responsible for macrophage-mediated LDL oxidation are not understood. One contributing mechanism may be the ability of macrophages to reduce transition metals. Reduced metals (such as Fe(II) or Cu(I)) rapidly react with lipid hydroperoxides, leading to the formation of reactive lipid radicals and conversion of the reduced metal to its oxidized form. We demonstrate here the ability of macrophages to reduce extracellular iron and copper and identify a contributing mechanism. Evidence is provided that a proportion of cell-mediated metal reduction is due to direct trans-plasma membrane electron transport. Glucagon suppressed both macrophage-mediated metal reduction and LDL oxidation. Although metal reduction was augmented when cells were provided with a substrate for thiol production, thiol export was not a strict requirement for cell-mediated metal reduction. Similarly, while the metal-dependent acceleration of LDL oxidation by macrophages was augmented by thiol production, macrophages could still promote LDL oxidation when thiol export was minimized (by substrate limitation). This study identifies a novel mechanism that may contribute to macrophage-mediated LDL oxidation and may also reveal potential new strategies for the inhibition of this process. Oxidation of low density lipoprotein (LDL) results in changes to the lipoprotein that are potentially atherogenic. Numerous studies have shown that macrophages cultured in vitro can promote LDL oxidation via a transition metal-dependent process, yet the exact mechanisms that are responsible for macrophage-mediated LDL oxidation are not understood. One contributing mechanism may be the ability of macrophages to reduce transition metals. Reduced metals (such as Fe(II) or Cu(I)) rapidly react with lipid hydroperoxides, leading to the formation of reactive lipid radicals and conversion of the reduced metal to its oxidized form. We demonstrate here the ability of macrophages to reduce extracellular iron and copper and identify a contributing mechanism. Evidence is provided that a proportion of cell-mediated metal reduction is due to direct trans-plasma membrane electron transport. Glucagon suppressed both macrophage-mediated metal reduction and LDL oxidation. Although metal reduction was augmented when cells were provided with a substrate for thiol production, thiol export was not a strict requirement for cell-mediated metal reduction. Similarly, while the metal-dependent acceleration of LDL oxidation by macrophages was augmented by thiol production, macrophages could still promote LDL oxidation when thiol export was minimized (by substrate limitation). This study identifies a novel mechanism that may contribute to macrophage-mediated LDL oxidation and may also reveal potential new strategies for the inhibition of this process. INTRODUCTIONThe oxidative modification of LDL 1The abbreviations used are: LDLlow density lipoproteinMDMmonocyte-derived macrophage(s)TPMETtrans-plasma membrane electron transportBCSbathocuproinedisulfonic acidBPSbathophenanthrolinedisulfonic acidDTNB5,5′-dithiobis(nitrobenzoic acid)FCCPcarbonyl cyanide p-trifluoromethoxyphenylhydrazoneHPLChigh performance liquid chromatographymPMmurine resident peritoneal macrophage(s)PBSphosphate-buffered salineHBSSHanks' balanced salt solutionCEcholesteryl ester. results in numerous changes to the lipoprotein that are potentially atherogenic (1Steinbrecher U.P. Zhang H.F. Lougheed M. Free Radical Biol. & Med. 1990; 9: 155-168Crossref PubMed Scopus (565) Google Scholar, 2Steinberg D. Parthasarathy S. Carew T.E. Khoo J.C. Witztum J.L. N. Engl. J. Med. 1989; 320: 915-924Crossref PubMed Google Scholar). In vitro copper-oxidized LDL can promote the accumulation of cholesterol in macrophages (3Steinbrecher U.P. Witztum J.L. Parthasarathy S. Steinberg D. Arterioscler. Thromb. 1987; 7: 135-143Crossref Google Scholar, 4Steinbrecher U.P. Parthasarathy S. Leake D.S. Witztum J.L. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 3883-3887Crossref PubMed Scopus (1405) Google Scholar) and stimulate monocyte recruitment (5Cushing S.D. Berliner J.A. Valente A.J. Territo M.C. Navab M. Parhami F. Gerrity R. Schwartz C.J. Fogelman A.M. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 5134-5138Crossref PubMed Scopus (962) Google Scholar) and adhesion (6Berliner J.A. Territo M.C. Sevanian A. Ramin S. Kim J.A. Bamshad B. Esterson M. Fogelman A.M. J. Clin. Invest. 1990; 85: 1260-1266Crossref PubMed Scopus (763) Google Scholar) to endothelial cells and be cytotoxic (7Hessler J.R. Morel D.W. Lewis L.J. Chisolm G.M. Arteriosclerosis. 1983; 3: 215-222Crossref PubMed Google Scholar). Most of the cell types present in the intima of arteries (including macrophages) can stimulate the oxidation of LDL in vitro (8Jessup W. Rankin S.M. De W.C. Hoult J.R. Scott J. Leake D.S. Biochem. J. 1990; 265: 399-405Crossref PubMed Scopus (272) Google Scholar, 9Heinecke J.W. Baker L. Rosen H. Chait A. J. Clin. Invest. 1986; 77: 757-761Crossref PubMed Scopus (429) Google Scholar, 10Henriksen T. Mahoney E.M. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 6499-6503Crossref PubMed Scopus (811) Google Scholar, 11Lamb D.J. Wilkins G.M. Leake D.S. Atherosclerosis. 1992; 92: 187-192Abstract Full Text PDF PubMed Scopus (54) Google Scholar, 12Garner B. Jessup W. Redox Rep. 1996; 2: 97-104Crossref PubMed Scopus (25) Google Scholar), and there is evidence for the presence of oxidized LDL in atherosclerotic plaque (13Palinski W. Rosenfeld M.E. Yla H.S. Gurtner G.C. Socher S.S. Butler S.W. Parthasarathy S. Carew T.E. Steinberg D. Witztum J.L. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1372-1376Crossref PubMed Scopus (1335) Google Scholar, 14Rosenfeld M.E. Palinski W. Yla H.S. Carew T.E. Toxicol. Pathol. 1990; 18: 560-571Crossref PubMed Scopus (44) Google Scholar). The presence of transition metals (either deliberately added or adventitious) in the culture medium appears to be an absolute requirement for cell-mediated oxidation of LDL in vitro, indicating that the activity of cells is to ongoing metal-dependent oxidation (12Garner B. Jessup W. Redox Rep. 1996; 2: 97-104Crossref PubMed Scopus (25) Google Scholar, 15Christen S. Thomas S.R. Garner B. Stocker R. J. Clin. Invest. 1994; 93: 2149-2158Crossref PubMed Scopus (85) Google Scholar). There is also evidence for the presence of transition metals in plaque (16Hunter G.C. Dubick M.A. Keen C.L. Eskelson C.D. Proc. Soc. Exp. Biol. Med. 1991; 196: 273-279Crossref PubMed Scopus (56) Google Scholar, 17Smith C. Mitchinson M.J. Aruoma O.I. Halliwell B. Biochem. J. 1992; 286: 901-905Crossref PubMed Scopus (405) Google Scholar), and it is known that physiologically relevant forms of both iron (e.g. hemin and ferritin) and copper (e.g. ceruloplasmin) can promote LDL oxidation in vitro, particularly under conditions related to inflammation (17Smith C. Mitchinson M.J. Aruoma O.I. Halliwell B. Biochem. J. 1992; 286: 901-905Crossref PubMed Scopus (405) Google Scholar, 18Balla G. Jacob H.S. Eaton J.W. Belcher J.D. Vercellotti G.M. Arterioscler. Thromb. 1991; 11: 1700-1711Crossref PubMed Scopus (384) Google Scholar, 19Ehrenwald E. Chisolm G.M. Fox P.L. J. Clin. Invest. 1994; 93: 1493-1501Crossref PubMed Scopus (238) Google Scholar). These studies indicate (but do not prove) that metal-catalyzed LDL oxidation could be one contributing factor in the generation of oxidized LDL during atherosclerosis. It is therefore important to define the mechanisms that underlie the metal-dependent acceleration of LDL oxidation by macrophages, quantitatively one of the most important cell types present in the developing atherosclerotic lesion (20Faggiotto A. Ross R. Harker L. Arteriosclerosis. 1984; 4: 323-340Crossref PubMed Google Scholar), to more completely understand the etiology of this disease.Several cellular mechanisms have been proposed to contribute to the oxidative modification of LDL (12Garner B. Jessup W. Redox Rep. 1996; 2: 97-104Crossref PubMed Scopus (25) Google Scholar, 21Jessup W. Leake D.S. Rice-Evans C. Bruckdorfer K.R. Oxidative Stress, Lipoproteins and Cardiovascular Function. Portland Press Ltd., London1995: 99-130Google Scholar). One potential mechanism is the cell-mediated reduction of transition metals, which might facilitate lipid hydroperoxide (L-OOH) decomposition and chain peroxidation (22Esterbauer H. Gebicki J. Puhl H. Jurgens G. Free Radical Biol. & Med. 1992; 13: 341-390Crossref PubMed Scopus (2132) Google Scholar) (Equations 1 and 2).Mn++e−(cell−derived)→M(n−1)+(Eq. 1) L−OOH+M(n−1)+→L−O·+OH−+Mn+(Eq. 2) Such lipid hydroperoxides are present in atherosclerotic plaque (23Suarna C. Dean R.T. May J. Stocker R. Arterioscler. Thromb. 1995; 15: 1616-1624Crossref Scopus (308) Google Scholar). However, mechanisms of macrophage-mediated transition metal reduction have not been studied. One possible cell-derived extracellular reductant is O2, but O2 is clearly not a rate-limiting species for the accelerated oxidation of LDL by murine macrophages (24Jessup W. Simpson J.A. Dean R.T. Atherosclerosis. 1993; 99: 107-120Abstract Full Text PDF PubMed Scopus (59) Google Scholar) or human monocyte-derived macrophages (MDM) (25Garner B. Dean R.T. Jessup W. Biochem. J. 1994; 301: 421-428Crossref PubMed Scopus (46) Google Scholar). Several studies have highlighted the importance of cellular thiol production in the acceleration of LDL oxidation (26Heinecke J.W. Rosen H. Suzuki L.A. Chait A. J. Biol. Chem. 1987; 262: 10098-10103Abstract Full Text PDF PubMed Google Scholar, 27Heinecke J.W. Kawamura M. Suzuki L. Chait A. J. Lipid Res. 1993; 34: 2051-2061Abstract Full Text PDF PubMed Google Scholar, 28Sparrow C.P. Olszewski J. J. Lipid Res. 1993; 34: 1219-1228Abstract Full Text PDF PubMed Google Scholar, 29Graham A. Wood J.L. O'Leary V.J. Stone D. Free Radical Res. 1994; 21: 295-308Crossref PubMed Scopus (26) Google Scholar), and it has been suggested that thiol-derived and oxygen-derived free radicals are responsible for these effects (30Parthasarathy S. Biochim. Biophys. Acta. 1987; 917: 337-340Crossref PubMed Scopus (192) Google Scholar). An alternative hypothesis could be that cell-derived thiols maintain transition metals in a reduced form, i.e. a state that confers high reactivity with lipid hydroperoxides. Such reduction of copper and iron by thiols (31Tien M. Bucher J.R. Aust S.D. Biochem. Biophys. Res. Commun. 1982; 107: 279-285Crossref PubMed Scopus (133) Google Scholar) and other molecules (32Miller D.M. Aust S.D. Arch. Biochem. Biophys. 1989; 271: 113-119Crossref PubMed Scopus (253) Google Scholar) is well known to promote lipid peroxidation (up to a critical reductant concentration beyond which inhibition of peroxidation often occurs) (27Heinecke J.W. Kawamura M. Suzuki L. Chait A. J. Lipid Res. 1993; 34: 2051-2061Abstract Full Text PDF PubMed Google Scholar, 31Tien M. Bucher J.R. Aust S.D. Biochem. Biophys. Res. Commun. 1982; 107: 279-285Crossref PubMed Scopus (133) Google Scholar).Since previous studies demonstrated extracellular transition metal reduction by a direct trans-plasma membrane electron transport (TPMET) system in a variety of mammalian cells (33Crane F.L. Sun I.L. Clark M.G. Grebing C. Löw H. Biochim. Biophys. Acta. 1985; 811: 233-264Crossref PubMed Scopus (399) Google Scholar), we here sought evidence for such a system in macrophages. This system, which has been previously characterized by its ability to reduce extracellular ferricyanide, utilizes internal NADH as an electron donor (34Goldenberg H. Crane F.L. Morré D.J. J. Biol. Chem. 1979; 254: 2491-2498Abstract Full Text PDF PubMed Google Scholar), and transport of electrons out of the cell is accompanied by proton movement (35Sun I.L. Crane F.L. Grebing C. Löw H. J. Bioenerg. Biomembr. 1984; 16: 583-595Crossref PubMed Scopus (62) Google Scholar). We investigated the TPMET system within a broader study of the mechanisms responsible for macrophage-mediated transition metal reduction and so could assess the possible contribution of both thiol-dependent and -independent metal reduction to the process of cell-mediated LDL oxidation. Our hypothesis was that macrophages' ability to promote LDL oxidation is related to their ability to reduce transition metals and that a direct macrophage plasma membrane electron transport system may account for a significant proportion of macrophage-mediated metal reduction.DISCUSSIONThis study demonstrated the ability of macrophages to reduce transition metals. Furthermore, we have attempted to delineate the mechanisms that underlie this process and their relationship to macrophage-mediated LDL oxidation.Cystine-independent Cell-mediated LDL OxidationOur studies show that macrophages are capable of promoting LDL oxidation in the absence of an extracellular substrate for thiol production. Careful assessment of data provided in previous reports that claimed a critical role for cell-derived thiols in LDL oxidation also showed that cell-mediated LDL oxidation was significantly greater than in parallel cell-free conditions even in thiol-free media. Thus, the monocytic THP-1 cell line (29Graham A. Wood J.L. O'Leary V.J. Stone D. Free Radical Res. 1994; 21: 295-308Crossref PubMed Scopus (26) Google Scholar) and the RECB4 endothelial cell line (28Sparrow C.P. Olszewski J. J. Lipid Res. 1993; 34: 1219-1228Abstract Full Text PDF PubMed Google Scholar) promoted LDL oxidation significantly (versus cell-free controls) in the absence of cystine, but in the presence of transition metals (0.01 μM copper and 3.0 μM iron). Santanam and Parthasarathy (54Santanam N. Parthasarathy S. J. Lipid Res. 1995; 36: 2203-2211Abstract Full Text PDF PubMed Google Scholar) have also recently argued that the cellular cysteine generation is not important for LDL oxidation.This study has confirmed the ability of macrophages to promote LDL oxidation in the presence of 0.01 μM copper and 3.0 μM iron and in the absence of cystine. In the two studies discussed above, as well as in the work presented here, addition of cystine to culture medium enhanced basal cell-mediated LDL oxidation, but not cell-free oxidation (28Sparrow C.P. Olszewski J. J. Lipid Res. 1993; 34: 1219-1228Abstract Full Text PDF PubMed Google Scholar, 29Graham A. Wood J.L. O'Leary V.J. Stone D. Free Radical Res. 1994; 21: 295-308Crossref PubMed Scopus (26) Google Scholar). However, the cellular mechanisms underlying the apparently thiol-independent acceleration of LDL oxidation have not been previously addressed.A role for cellular thiol production in cell-mediated LDL oxidation has been suggested to be due to the production of O2 by the extracellular oxidation of the thiol (26Heinecke J.W. Rosen H. Suzuki L.A. Chait A. J. Biol. Chem. 1987; 262: 10098-10103Abstract Full Text PDF PubMed Google Scholar, 30Parthasarathy S. Biochim. Biophys. Acta. 1987; 917: 337-340Crossref PubMed Scopus (192) Google Scholar). However, the inability of superoxide dismutase to prevent macrophage-mediated LDL oxidation argues against this as a predominant mechanism (24Jessup W. Simpson J.A. Dean R.T. Atherosclerosis. 1993; 99: 107-120Abstract Full Text PDF PubMed Scopus (59) Google Scholar). Macrophage-mediated transition metal reduction was investigated to understand the thiol-independent acceleration of LDL oxidation by these cells. A role for cell-derived thiols as enhancers of such cellular metal reduction was also examined. Cell-mediated metal reduction may stimulate LDL oxidation by reaction of reduced metal with lipoprotein hydroperoxides, causing propagation of lipid peroxidation.Macrophage-mediated Transition Metal ReductionMacrophages were able to reduce both iron and copper in the absence of a substrate for cellular thiol production at rates that could not be substantially accounted for by reductants released into the cell supernatant. When cystine was added to cells, the apparent cell-mediated copper reduction was enhanced after ≈1 h, and a larger proportion of this enhancement could be explained by exported thiols (≈85% of the supernatant's ability to reduce copper could be due to DTNB-detectable thiol). These results suggest that a proportion of cell-mediated metal reduction is due to direct electron transport and that, in the absence of a substrate for cell-derived thiols (i.e. when cystine is not supplied), this proportion is large. Evidence for copper reduction via a direct plasma membrane electron transport system was therefore sought by use of agents known to modulate similar systems (TPMET) in other cell types (33Crane F.L. Sun I.L. Clark M.G. Grebing C. Löw H. Biochim. Biophys. Acta. 1985; 811: 233-264Crossref PubMed Scopus (399) Google Scholar, 35Sun I.L. Crane F.L. Grebing C. Löw H. J. Bioenerg. Biomembr. 1984; 16: 583-595Crossref PubMed Scopus (62) Google Scholar, 51Alcain F.J. Löw H. Crane F.L. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7903-7906Crossref PubMed Scopus (25) Google Scholar). Macrophage-mediated copper reduction shared striking similarities with previous reports in its sensitivity to depletion of plasma membrane iron (51Alcain F.J. Löw H. Crane F.L. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7903-7906Crossref PubMed Scopus (25) Google Scholar, 55Alcain F.J. Villalba J.M. Löw H. Crane F.L. Navas P. Biochem. Biophys. Res. Commun. 1992; 186: 951-955Crossref PubMed Scopus (21) Google Scholar) and exposure to FCCP (52Löw H. Crane F.L. Grebing C. Isaksson M. Lindgren A. Sun I.L. J. Bioenerg. Biomembr. 1991; 23: 903-917Crossref PubMed Scopus (21) Google Scholar) or glucagon (53Clark M.G. Partick E.J. Crane F.L. Biochem. J. 1982; 204: 795-801Crossref PubMed Scopus (21) Google Scholar).Cell-mediated Metal Reduction Dominates over Other MechanismsOur data show that in the absence of cystine, cell-mediated metal reduction is much more extensive than that induced by other components of the system, notably LDL. The reduction of copper by LDL, with or without cells, was an order of magnitude smaller than the cellular contribution. This quantity (∼0.6 nmol) is similar to the amount of tocopherol present in LDL, consistent with previous reports that tocopherol in lipid systems can reduce transition metals stoichiometrically (e.g. 56Fukuzawa K. Kishikawa K. Tadokoro T. Tokumura A. Tsukatani H. Gebicki J.M. Arch. Biochem. Biophys. 1988; 260: 153-160Crossref PubMed Scopus (40) Google Scholar). Such data have also been obtained with isolated LDL (48Yoshida Y. Tsuchiya J. Niki E. Biochim. Biophys. Acta. 1994; 1200: 85-92Crossref PubMed Scopus (107) Google Scholar). In contrast, Lynch and Frei (57Lynch S.M. Frei B. J. Biol. Chem. 1995; 270: 5158-5163Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar) have claimed that LDL possesses a nonsaturable capacity to reduce copper in cell-free conditions, also measured by Cu(I)·BCS formation. This disparity may be explicable by two factors. First, the presence of selective reduced metal chelators can drive the metal toward the reduced chelated complexes (58Itabashi H. Umetsu K. Satoh K. Kawashima T. Anal. Sci. 1990; 6: 721-725Crossref Scopus (26) Google Scholar, 59van Reyk D. Dean R.T. Free Radical Res. 1996; 24: 55-60Crossref PubMed Scopus (12) Google Scholar). Second, the extensive Cu(I)·BCS generation by LDL (57Lynch S.M. Frei B. J. Biol. Chem. 1995; 270: 5158-5163Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar) may be due to the lipoprotein oxidation that occurred simultaneously. Many components of this pathway (e.g. hydroperoxides) reduce copper; thus, the metal reduction in this system may be partly a consequence of oxidation, rather than a determinant of it. In our study, LDL was not present during measurement of cellular metal reduction, so its oxidation could not contribute to the rates of copper reduction reported. It is possible that BCS could promote Cu(I) generation in the presence of MDM, leading to an overestimate of the rate and extent of cellular reduction. However, the low ratio of chelator to copper (2.5:1) used in this study and the saturability of cell-mediated copper reduction (Fig. 7) indicate that chelator-driven reduction was not a significant factor here.Involvement of Macrophage-mediated Transition Metal Reduction in LDL OxidationThe final objective of this work was to assess the impact of changes in cell-mediated metal reduction on cell-mediated LDL oxidation. Glucagon suppressed both macrophage-mediated copper reduction and LDL oxidation, consistent with our hypothesis that the cell's ability to promote LDL oxidation is dependent on its capacity to reduce transition metals. Since glucagon also inhibited macrophage-mediated LDL oxidation in media that contained cystine, TPMET-mediated metal reduction may remain a rate-limiting mechanism in LDL oxidation even when thiol export is operational. In agreement with our conclusion that TPMET activity may be central to LDL oxidation, two recent studies have shown that other compounds that modulate its activity also modulate metal-dependent cell-mediated LDL oxidation. Thus, insulin increases ferricyanide reduction by HeLa cells (60Sun I.L. Crane F.L. Löw H. Grebing C. Biochem. Biophys. Res. Commun. 1984; 125: 649-654Crossref PubMed Scopus (52) Google Scholar, 61Sun I.L. Crane F.L. Grebing C. Löw H. Exp. Cell Res. 1985; 156: 528-536Crossref PubMed Scopus (53) Google Scholar) and human erythrocytes (62Dormandy T.L. Zarday Z. J. Physiol. (Lond.). 1965; 180: 684-707Crossref Scopus (27) Google Scholar) and accelerates LDL oxidation by peripheral blood mononuclear cells (63Rifici V.A. Schneider S.H. Khachadurian A.K. Atherosclerosis. 1994; 107: 99-108Abstract Full Text PDF PubMed Scopus (37) Google Scholar). Actinomycin D inhibits both cellular TPMET activity (64Sun I. Crane F.L. Biochem. Biophys. Res. Commun. 1981; 101: 68-75Crossref PubMed Scopus (15) Google Scholar) and macrophage-mediated LDL oxidation (65Aviram M. Rosenblat M. J. Lipid Res. 1994; 35: 385-398Abstract Full Text PDF PubMed Google Scholar). While agents that modulate cellular TPMET activity may have other effects that are relevant to the cells' ability to promote LDL oxidation (for example, modulation of thiol export), the possibility that cellular TPMET capabilities are key to the process of cell-mediated LDL oxidation remains plausible. That all mammalian cells studied so far display TPMET activity (33Crane F.L. Sun I.L. Clark M.G. Grebing C. Löw H. Biochim. Biophys. Acta. 1985; 811: 233-264Crossref PubMed Scopus (399) Google Scholar) indicates that many cell types could promote the metal-dependent oxidation of LDL by a similar mechanism.In conclusion, the results presented in this paper argue that macrophages can both accelerate the metal-dependent oxidation of LDL and reduce transition metals when cellular thiol production is minimized by omission of extracellular cystine. The cellular reducing activity shares many features with a TPMET system previously characterized in other cell types. Cellular TPMET activity appears to be amenable to modulation by hormones, growth factors, and drugs (33Crane F.L. Sun I.L. Clark M.G. Grebing C. Löw H. Biochim. Biophys. Acta. 1985; 811: 233-264Crossref PubMed Scopus (399) Google Scholar). Thus, controlling the processes that contribute to cell-mediated transition metal redox cycling may provide an opportunity for controlling the formation of copper-oxidized LDL. INTRODUCTIONThe oxidative modification of LDL 1The abbreviations used are: LDLlow density lipoproteinMDMmonocyte-derived macrophage(s)TPMETtrans-plasma membrane electron transportBCSbathocuproinedisulfonic acidBPSbathophenanthrolinedisulfonic acidDTNB5,5′-dithiobis(nitrobenzoic acid)FCCPcarbonyl cyanide p-trifluoromethoxyphenylhydrazoneHPLChigh performance liquid chromatographymPMmurine resident peritoneal macrophage(s)PBSphosphate-buffered salineHBSSHanks' balanced salt solutionCEcholesteryl ester. results in numerous changes to the lipoprotein that are potentially atherogenic (1Steinbrecher U.P. Zhang H.F. Lougheed M. Free Radical Biol. & Med. 1990; 9: 155-168Crossref PubMed Scopus (565) Google Scholar, 2Steinberg D. Parthasarathy S. Carew T.E. Khoo J.C. Witztum J.L. N. Engl. J. Med. 1989; 320: 915-924Crossref PubMed Google Scholar). In vitro copper-oxidized LDL can promote the accumulation of cholesterol in macrophages (3Steinbrecher U.P. Witztum J.L. Parthasarathy S. Steinberg D. Arterioscler. Thromb. 1987; 7: 135-143Crossref Google Scholar, 4Steinbrecher U.P. Parthasarathy S. Leake D.S. Witztum J.L. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 3883-3887Crossref PubMed Scopus (1405) Google Scholar) and stimulate monocyte recruitment (5Cushing S.D. Berliner J.A. Valente A.J. Territo M.C. Navab M. Parhami F. Gerrity R. Schwartz C.J. Fogelman A.M. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 5134-5138Crossref PubMed Scopus (962) Google Scholar) and adhesion (6Berliner J.A. Territo M.C. Sevanian A. Ramin S. Kim J.A. Bamshad B. Esterson M. Fogelman A.M. J. Clin. Invest. 1990; 85: 1260-1266Crossref PubMed Scopus (763) Google Scholar) to endothelial cells and be cytotoxic (7Hessler J.R. Morel D.W. Lewis L.J. Chisolm G.M. Arteriosclerosis. 1983; 3: 215-222Crossref PubMed Google Scholar). Most of the cell types present in the intima of arteries (including macrophages) can stimulate the oxidation of LDL in vitro (8Jessup W. Rankin S.M. De W.C. Hoult J.R. Scott J. Leake D.S. Biochem. J. 1990; 265: 399-405Crossref PubMed Scopus (272) Google Scholar, 9Heinecke J.W. Baker L. Rosen H. Chait A. J. Clin. Invest. 1986; 77: 757-761Crossref PubMed Scopus (429) Google Scholar, 10Henriksen T. Mahoney E.M. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 6499-6503Crossref PubMed Scopus (811) Google Scholar, 11Lamb D.J. Wilkins G.M. Leake D.S. Atherosclerosis. 1992; 92: 187-192Abstract Full Text PDF PubMed Scopus (54) Google Scholar, 12Garner B. Jessup W. Redox Rep. 1996; 2: 97-104Crossref PubMed Scopus (25) Google Scholar), and there is evidence for the presence of oxidized LDL in atherosclerotic plaque (13Palinski W. Rosenfeld M.E. Yla H.S. Gurtner G.C. Socher S.S. Butler S.W. Parthasarathy S. Carew T.E. Steinberg D. Witztum J.L. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1372-1376Crossref PubMed Scopus (1335) Google Scholar, 14Rosenfeld M.E. Palinski W. Yla H.S. Carew T.E. Toxicol. Pathol. 1990; 18: 560-571Crossref PubMed Scopus (44) Google Scholar). The presence of transition metals (either deliberately added or adventitious) in the culture medium appears to be an absolute requirement for cell-mediated oxidation of LDL in vitro, indicating that the activity of cells is to ongoing metal-dependent oxidation (12Garner B. Jessup W. Redox Rep. 1996; 2: 97-104Crossref PubMed Scopus (25) Google Scholar, 15Christen S. Thomas S.R. Garner B. Stocker R. J. Clin. Invest. 1994; 93: 2149-2158Crossref PubMed Scopus (85) Google Scholar). There is also evidence for the presence of transition metals in plaque (16Hunter G.C. Dubick M.A. Keen C.L. Eskelson C.D. Proc. Soc. Exp. Biol. Med. 1991; 196: 273-279Crossref PubMed Scopus (56) Google Scholar, 17Smith C. Mitchinson M.J. Aruoma O.I. Halliwell B. Biochem. J. 1992; 286: 901-905Crossref PubMed Scopus (405) Google Scholar), and it is known that physiologically relevant forms of both iron (e.g. hemin and ferritin) and copper (e.g. ceruloplasmin) can promote LDL oxidation in vitro, particularly under conditions related to inflammation (17Smith C. Mitchinson M.J. Aruoma O.I. Halliwell B. Biochem. J. 1992; 286: 901-905Crossref PubMed Scopus (405) Google Scholar, 18Balla G. Jacob H.S. Eaton J.W. Belcher J.D. Vercellotti G.M. Arterioscler. Thromb. 1991; 11: 1700-1711Crossref PubMed Scopus (384) Google Scholar, 19Ehrenwald E. Chisolm G.M. Fox P.L. J. Clin. Invest. 1994; 93: 1493-1501Crossref PubMed Scopus (238) Google Scholar). These studies indicate (but do not prove) that metal-catalyzed LDL oxidation could be one contributing factor in the generation of oxidized LDL during atherosclerosis. It is therefore important to define the mechanisms that underlie the metal-dependent acceleration of LDL oxidation by macrophages, quantitatively one of the most important cell types present in the developing atherosclerotic lesion (20Faggiotto A. Ross R. Harker L. Arteriosclerosis. 1984; 4: 323-340Crossref PubMed Google Scholar), to more completely understand the etiology of this disease.Several cellular mechanisms have been proposed to contribute to the oxidative modification of LDL (12Garner B. Jessup W. Redox Rep. 1996; 2: 97-104Crossref PubMed Scopus (25) Google Scholar, 21Jessup W. Leake D.S. Rice-Evans C. Bruckdorfer K.R. Oxidative Stress, Lipoproteins and Cardiovascular Function. Portland Press Ltd., London1995: 99-130Google Scholar). One potential mechanism is the cell-mediated reduction of transition metals, which might facilitate lipid hydroperoxide (L-OOH) decomposition and chain peroxidation (22Esterbauer H. Gebicki J. Puhl H. Jurgens G. Free Radical Biol. & Med. 1992; 13: 341-390Crossref PubMed Scopus (2132) Google Scholar) (Equations 1 and 2).Mn++e−(cell−derived)→M(n−1)+(Eq. 1) L−OOH+M(n−1)+→L−O·+OH−+Mn+(Eq. 2) Such lipid hydroperoxides are present in atherosclerotic plaque (23Suarna C. Dean R.T. May J. Stocker R. Arterioscler. Thromb. 1995; 15: 1616-1624Crossref Scopus (308) Google Scholar). However, mechanisms of macrophage-mediated transition metal reduction have not been studied. One possible cell-derived extracellular reductant is O2, but O2 is clearly not a rate-limiting species for the accelerated oxidation of LDL by murine macrophages (24Jessup W. Simpson J.A. Dean R.T. Atherosclerosis. 1993; 99: 107-120Abstract Full Text PDF PubMed Scopus (59) Google Scholar) or human monocyte-derived macrophages (MDM) (25Garner B. Dean R.T. Jessup W. Biochem. J. 1994; 301: 421-428Crossref PubMed Scopus (46) Google Scholar). Several studies have highlighted the importance of cellular thiol production in the acceleration of LDL oxidation (26Heinecke J.W. Rosen H. Suzuki L.A. Chait A. J. Biol. Chem. 1987; 262: 10098-10103Abstract Full Text PDF PubMed Google Scholar, 27Heinecke J.W. Kawamura M. Suzuki L. Chait A. J. Lipid Res. 1993; 34: 2051-2061Abstract Full Text PDF PubMed Google Scholar, 28Sparrow C.P. Olszewski J. J. Lipid Res. 1993; 34: 1219-1228Abstract Full Text PDF PubMed Google Scholar, 29Graham A. Wood J.L. O'Leary V.J. Stone D. Free Radical Res. 1994; 21: 295-308Crossref PubMed Scopus (26) Google Scholar), and it has been suggested that thiol-derived and oxygen-derived free radicals are responsible for these effects (30Parthasarathy S. Biochim. Biophys. Acta. 1987; 917: 337-340Crossref PubMed Scopus (192) Google Scholar). An alternative hypothesis could be that cell-derived thiols maintain transition metals in a reduced form, i.e. a state that confers high reactivity with lipid hydroperoxides. Such reduction of copper and iron by thiols (31Tien M. Bucher J.R. Aust S.D. Biochem. Biophys. Res. Commun. 1982; 107: 279-285Crossref PubMed Scopus (133) Google Scholar) and other molecules (32Miller D.M. Aust S.D. Arch. Biochem. Biophys. 1989; 271: 113-119Crossref PubMed Scopus (253) Google Scholar) is well known to promote lipid peroxidation (up to a critical reductant concentration beyond which inhibition of peroxidation often occurs) (27Heinecke J.W. Kawamura M. Suzuki L. Chait A. J. Lipid Res. 1993; 34: 2051-2061Abstract Full Text PDF PubMed Google Scholar, 31Tien M. Bucher J.R. Aust S.D. Biochem. Biophys. Res. Commun. 1982; 107: 279-285Crossref PubMed Scopus (133) Google Scholar).Since previous studies demonstrated extracellular transition metal reduction by a direct trans-plasma membrane electron transport (TPMET) system in a variety of mammalian cells (33Crane F.L. Sun I.L. Clark M.G. Grebing C. Löw H. Biochim. Biophys. Acta. 1985; 811: 233-264Crossref PubMed Scopus (399) Google Scholar), we here sought evidence for such a system in macrophages. This system, which has been previously characterized by its ability to reduce extracellular ferricyanide, utilizes internal NADH as an electron donor (34Goldenberg H. Crane F.L. Morré D.J. J. Biol. Chem. 1979; 254: 2491-2498Abstract Full Text PDF PubMed Google Scholar), and transport of electrons out of the cell is accompanied by proton movement (35Sun I.L. Crane F.L. Grebing C. Löw H. J. Bioenerg. Biomembr. 1984; 16: 583-595Crossref PubMed Scopus (62) Google Scholar). We investigated the TPMET system within a broader study of the mechanisms responsible for macrophage-mediated transition metal reduction and so could assess the possible contribution of both thiol-dependent and -independent metal reduction to the process of cell-mediated LDL oxidation. Our hypothesis was that macrophages' ability to promote LDL oxidation is related to their ability to reduce transition metals and that a direct macrophage plasma membrane electron transport system may account for a significant proportion of macrophage-mediated metal reduction." @default.
• W2122238876 created "2016-06-24" @default.
• W2122238876 creator A5026489700 @default.
• W2122238876 creator A5030922535 @default.
• W2122238876 creator A5032367595 @default.
• W2122238876 creator A5044406835 @default.
• W2122238876 date "1997-03-01" @default.
• W2122238876 modified "2023-09-29" @default.
• W2122238876 title "Direct Copper Reduction by Macrophages" @default.
• W2122238876 cites W1480437199 @default.
• W2122238876 cites W1509255658 @default.
• W2122238876 cites W1516636175 @default.
• W2122238876 cites W1546475417 @default.
• W2122238876 cites W1562522900 @default.
• W2122238876 cites W1650689119 @default.
• W2122238876 cites W1810073570 @default.
• W2122238876 cites W1824744945 @default.
• W2122238876 cites W1965106723 @default.
• W2122238876 cites W1966759550 @default.
• W2122238876 cites W1968679020 @default.
• W2122238876 cites W1969458169 @default.
• W2122238876 cites W1970185441 @default.
• W2122238876 cites W1982208715 @default.
• W2122238876 cites W1984393490 @default.
• W2122238876 cites W1986350080 @default.
• W2122238876 cites W1986481396 @default.
• W2122238876 cites W1997745709 @default.
• W2122238876 cites W2000072536 @default.
• W2122238876 cites W2005095476 @default.
• W2122238876 cites W2005230846 @default.
• W2122238876 cites W2008819827 @default.
• W2122238876 cites W2013513127 @default.
• W2122238876 cites W2020478341 @default.
• W2122238876 cites W2022050793 @default.
• W2122238876 cites W2022628608 @default.
• W2122238876 cites W2032559513 @default.
• W2122238876 cites W2036852690 @default.
• W2122238876 cites W2037540167 @default.
• W2122238876 cites W2038818753 @default.
• W2122238876 cites W2040579726 @default.
• W2122238876 cites W2040844673 @default.
• W2122238876 cites W2044900626 @default.
• W2122238876 cites W2047327988 @default.
• W2122238876 cites W2050795431 @default.
• W2122238876 cites W2063021149 @default.
• W2122238876 cites W2066545983 @default.
• W2122238876 cites W2070120470 @default.
• W2122238876 cites W2070951814 @default.
• W2122238876 cites W2071120585 @default.
• W2122238876 cites W2073464812 @default.
• W2122238876 cites W2080696938 @default.
• W2122238876 cites W2082327493 @default.
• W2122238876 cites W2094523631 @default.
• W2122238876 cites W2104992264 @default.
• W2122238876 cites W2113553969 @default.
• W2122238876 cites W2114462793 @default.
• W2122238876 cites W2145371752 @default.
• W2122238876 cites W2161165626 @default.
• W2122238876 cites W2163485744 @default.
• W2122238876 cites W2171289458 @default.
• W2122238876 cites W2283083940 @default.
• W2122238876 cites W2317431465 @default.
• W2122238876 cites W2326202471 @default.
• W2122238876 cites W2330739169 @default.
• W2122238876 cites W2331476903 @default.
• W2122238876 cites W2395792778 @default.
• W2122238876 cites W2400802530 @default.
• W2122238876 cites W2408576957 @default.
• W2122238876 cites W2467053015 @default.
• W2122238876 cites W4255121565 @default.
• W2122238876 cites W88991601 @default.
• W2122238876 doi "https://doi.org/10.1074/jbc.272.11.6927" @default.
• W2122238876 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/9054380" @default.
• W2122238876 hasPublicationYear "1997" @default.
• W2122238876 type Work @default.
• W2122238876 sameAs 2122238876 @default.
• W2122238876 citedByCount "49" @default.
• W2122238876 crossrefType "journal-article" @default.
• W2122238876 hasAuthorship W2122238876A5026489700 @default.
• W2122238876 hasAuthorship W2122238876A5030922535 @default.
• W2122238876 hasAuthorship W2122238876A5032367595 @default.
• W2122238876 hasAuthorship W2122238876A5044406835 @default.
• W2122238876 hasBestOaLocation W21222388761 @default.
• W2122238876 hasConcept C111335779 @default.
• W2122238876 hasConcept C178790620 @default.
• W2122238876 hasConcept C185592680 @default.
• W2122238876 hasConcept C2524010 @default.
• W2122238876 hasConcept C33923547 @default.
• W2122238876 hasConcept C544778455 @default.
• W2122238876 hasConcept C86803240 @default.
• W2122238876 hasConcept C89423630 @default.
• W2122238876 hasConceptScore W2122238876C111335779 @default.
• W2122238876 hasConceptScore W2122238876C178790620 @default.
• W2122238876 hasConceptScore W2122238876C185592680 @default.
• W2122238876 hasConceptScore W2122238876C2524010 @default.
• W2122238876 hasConceptScore W2122238876C33923547 @default.
• W2122238876 hasConceptScore W2122238876C544778455 @default.
• W2122238876 hasConceptScore W2122238876C86803240 @default.

• next