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Autoinhibition of murine macrophage-mediated oxidation of low-density lipoprotein by nitric oxide synthesis

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      Abstract

      Murine peritoneal macrophages treated with γ-interferon and lipopolysaccharide (activated cells) oxidized low-density lipoprotein (LDL) less readily than unstimulated cells. Activated cells expressed the enzyme nitric oxide synthase, whose activity was measured by the accumulation of nitrite in the culture supernatant. Treatment of activated macrophages with the arginine analogue NG-monomethyl-arginine (NMMA) inhibited nitric oxide synthesis and restored the ability of the cells to oxidize LDL. This treatment had no effect on the ability of unstimulated cells to oxidize LDL. Similarly, LDL oxidation by activated macrophages in arginine-free Ham's F-10 medium was identical to that of unstimulated cells, whereas restoration of arginine to the medium was associated with nitrite secretion and a decline in LDL oxidation by activated cells only. An inverse relationship between nitric oxide synthesis and LDL oxidation was also demonstrated in the presence of diphenylene iodonium, a flavin analogue which is a potent inhibitor of nitric oxide synthase. Thus nitric oxide synthesis appears to mediate the suppression of LDL oxidation which is associated with the activation of mouse macrophages by γ-interferon and lipopolysaccharide.

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      References

        • Steinbrecher U.P.
        • Zhang H.
        • Lougheed M.
        Role of oxidatively modified LDL in atherosclerosis.
        Free Rad. Biol. Med. 1990; 9: 155
        • Henricksen T.
        • Mahoney E.M.
        • Steinberg D.
        Enhanced degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low-density lipoproteins.
        in: Proc. Nad. Acad. Sci. USA. 78. 1981: 6499
        • Steinbrecher U.P.
        Role of superoxide in endothelial-cell modification of low-density lipoproteins.
        Biochim. Biophys. Acta. 1988; 959: 20
        • Hiramatsu K.
        • Rosen H.
        • Heinecke J.W.
        • Wolfbauer G.
        • Chait A.
        Superoxide initiates oxidation of lowdensity lipoprotein by human monocytes.
        Arteriosclerosis. 1987; 7: 55
        • Cathcart M.A.
        • McNally A.K.
        • Morel D.W.
        • Chisholm G.M.
        Superoxide anion participation in human monocyte-mediated oxidation of low-density lipoprotein to a cytotoxin.
        J. Immunol. 1989; 142: 1963
        • Rankin S.M.
        • Parthasarathy S.
        • Steinberg D.
        Evidence for a dominant role of lipoxygenase(s) in the oxidation of LDL by mouse peritoneal macrophages.
        J. Lipid Res. 1991; 32: 449
        • McNally A.K.
        • Chisholm G.M.
        • Morel D.W.
        • Cathcart M.K.
        Activated human monocytes oxidize lowdensity lipoprotein by a lipoxygenase-dependent pathway.
        J. Immunol. 1990; 145: 254
        • Jessup W.
        • Darley-Usmar V.
        • O'Leary V.
        • Bedwell S.
        5-Lipoxygenase is not essential for macrophagemediated oxidation of low-density lipoprotein.
        Biochem. J. 1991; 278: 163
        • Jessup W.
        • Simpson J.A.
        • Dean R.T.
        Does superoxide have a role in macrophage-mediated oxidation of LDL?.
        Atherosclerosis. 1993; 99: 107
        • Sparrow C.P.
        • Olszewski J.
        Cellular oxidative modification of low density lipoprotein does not require lipoxygenases.
        in: Proc. Nail. Acad. Sci., USA. 89. 1992: 128
        • Nathan C.
        Nitric oxide as a secretory product of mammalian cells.
        FASEB J. 1992; 6: 3051
        • Beckman J.S.
        • Beckman T.W.
        • Chen J.
        • Marshall P.A.
        • Freeman B.A.
        Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide.
        in: Proc. Natl. Acad. Sci., USA. 87. 1990: 1620
        • Hogg N.
        • Darley-Usmar V.M.
        • Wilson M.T.
        • Moncada S.
        Production of hydroxyl radicals from the simultaneous generation of superoxide and nitric oxide.
        Biochem. J. 1992; 281: 419
        • Radi R.
        • Beckman J.S.
        • Bush K.M.
        • Freeman B.A.
        Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxide.
        Arch. Biochem. Biophys. 1991; 288: 481
        • Moreno J.J.
        • Pryor W.A.
        Inactivation of α-1-proteinase inhibitor by peroxynitrite.
        Chem. Res. Toxicol. 1992; 5 (1992): 425
        • Radi R.
        • Beckman J.S.
        • Bush K.M.
        • Freeman B.A.
        Peroxynitrite oxidation of sulphydryls.
        J. Biol. Chem. 1991; 266: 4244
        • Jessup W.
        • Mohr D.
        • Gieseg S.P.
        • Dean R.T.
        • Stocker R.
        The participation of nitric oxide in cell-freeand its restriction of macrophage-mediated oxidation of low-density lipoprotein, Biochim.
        Biophys. Acta. 1992; 1180: 73
        • Darley-Usmar V.M.
        • Hogg N.
        • O'Leary V.J.
        • Wilson M.T.
        • Moncada S.
        The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low-density lipoprotein.
        Free Rad. Res. Commun. 1992; 17: 9
        • Chung B.H.
        • Segrest J.P.
        • Ray M.J.
        • Brunzell J.D.
        • Hokason J.E.
        • Krauss R.M.
        • Beaudrie K.
        • Cone J.T.
        Single vertical spin density gradient ultracentrifugation.
        Methods Enzymol. 1986; 128: 181
        • Bilheimer D.W.
        • Eisenberg S.
        • Levy R.I.
        The metabolism of very low density lipoproteins: I. Preliminary in vitro and in vivo observations.
        Biochim. Biophys. Acta. 1972; 260: 212
        • Jessup W.
        • Mander E.L.
        • Dean R.T.
        The intracellular storage and turnover of apolipoprotein B of oxidized LDL in macrophages.
        Biochim. Biophys. Acta. 1992; 1126: 167
        • Thomas S.M.
        • Jessup W.
        • Gebicki J.M.
        • Dean R.T.
        A continuous flow automated assay for iodometric estimation of hydroperoxides.
        Anal. Biochem. 1988; 176: 353
        • Burton G.W.
        • Webb A.
        • Ingold K.U.
        A mild, rapid and efficient method of lipid extraction for use in determining vitamin E/lipid ratios.
        Lipids. 1985; 20: 29
        • Ding A.H.
        • Nathan C.F.
        • Stuehr D.J.
        Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages: comparison of activating cytokines and evidence for independent production.
        J. Immunol. 1988; 141 (1988): 2407
        • Gross S.S.
        • Stuehr D.J.
        • Aisaka K.
        • Jaffe E.A.
        • Levi R.
        • Griffith O.W.
        Macrophage and endothelial cell nitric oxide synthesis: cell-type selective inhibition by NG-aminoarginine, NG-nitroarginine and NG-methylarginine.
        Biochem. Biophys. Res. Commun. 1990; 170: 96
        • Stuehr D.J.
        • Fasehun O.A.
        • Kwon N.S.
        • Gross S.S.
        • Gonzalez J.A.
        • Levi R.
        • Nathan C.F.
        Inhibition of macrophage and endothelial nitric oxide synthase by diphenylene iodonium and its analogues.
        FASEB J. 1991; 5: 98
        • Hancock J.T.
        • Jones O.T.G.
        The inhibition by diphenylene iodonium and its analogues of superoxide generation by macrophages.
        Biochem. J. 1987; 242: 103
        • Bedwell S.
        • Dean R.T.
        • Jessup W.
        The action of defined oxygen-centered free radicals on LDL structure and metabolism.
        Biochem. J. 1989; 262: 707
        • Yates M.T.
        • Lambert L.E.
        • Whitten J.P.
        • McDonald I.
        • Mano M.
        • Ku G.
        • Mao S.J.T.
        A protective role for nitric oxide in the oxidative modification of low-density lipoproteins by mouse macrophages.
        FEBS Lett. 1992; 309: 135
        • Arnold W.P.
        • Mittal C.K.
        • Katsuki S.
        • Murad F.
        Nitric oxide activates soluble guanylate cyclase and increases guanosine 3′,5′-cyclic monophosphate levels in various tissue preparations.
        in: Proc. Natl. Acad. Sci. USA. 74. 1977: 3203
        • Stuehr D.J.
        • Nathan C.F.
        Nitric oxide: a macrophage product responsible for cytostasis and respiratory inhibition in tumour target cells.
        J. Exp. Med. 1989; 169: 1543
        • Kanner J.
        • Harel S.
        • Granit R.
        Nitric oxide, an inhibitor of lipid oxidation by lipoxygenase, cyclooxygenase and hemoglobin.
        Lipids. 1992; 27: 46
        • Hansson G.K.
        • Jonasson L.
        • Seifert P.S.
        • Stemme S.
        Immune mechanisms in atherosclerosis.
        Arteriosclerosis. 1989; 9: 567
        • Nathan C.
        A commentary: inducible nitric oxide synthase.
        Res. Immunol. 1991; 147: 600
        • Kilbourn R.G.
        • Belloni P.
        Endothelial cell production of nitric oxides in response to interferon in combination with tumour necrosis factor, interleukin-1 or endotoxin.
        J. Natl. Cancer Inst. 1990; 82: 772
        • Hunt N.C.
        • Goldin R.D.
        Nitric oxide production by monocytes in alcoholic liver disease.
        J. Hepatol. 1992; 14: 146
        • Nussler A.K.
        • Di Silvio M.
        • Billiar T.R.
        • Hoffman R.A.
        • Geller D.A.
        • Selby R.
        • Madariaga J.
        • Simmons R.L.
        Stimulation of the nitric oxide synthase pathway in human hepatocytes by cytokines and endotoxin.
        J. Exp. Med. 1992; 176: 261
        • Sherman M.P.
        • Loro M.L.
        • Wong V.Z.
        • Tashkin D.P.
        Cytokine- and Pneumocystis carinii-induced l-arginine oxidation by murine and human pulmonary alveolar macrophages.
        J. Protozool. 1991; 38: 2345
        • Petros A.
        • Bennet D.
        • Valiance P.
        Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock.
        Lancet. 1991; 338: 1557
        • Schmidt H.H.
        • Zernikow B.
        • Baeblich S.
        • Bohme E.
        Basal and stimulated formation and release of l-argininederived nitrogen oxides from cultured endothelial cells.
        J. Pharm. Exp. Ther. 1990; 254: 591
        • Chin J.H.
        • Azhar S.
        • Hoffman B.B.
        Inactivation of endothelial derived relaxing factor by oxidized lipoproteins.
        J. Clin. Invest. 1992; 89: 10
        • Jorens P.G.
        • Rosseneu M.
        • Devreese A-M.
        • Bult H.
        • Marescau B.
        • Herman A.G.
        Diminished capacity to release metabolites of nitric oxide synthases in macro phages loaded with oxidized low-density lipoproteins.
        Eur. J. Pharmacol. 1992; 212: 113