Advertisement

Homocysteine strongly enhances metal-catalyzed LDL oxidation in the presence of cystine and cysteine

      Abstract

      Here we show that homocysteine stimulates low density lipoprotein (LDL) oxidation at copper(II) concentrations causing only a slight oxidation of LDL lipids. LDL oxidation by homocysteine and copper(II) is further enhanced in the presence of cystine, although cystine alone does not stimulate LDL oxidation with copper(II). Similarly, a combination of cysteine with homocysteine provoked a more than additive increase of oxidation. Simultaneous presence of cysteine and homocystine also resulted in a more than additive oxidative effect which was not statistically significant, however. Stimulation of LDL oxidation in the presence of homocysteine by cystine was also observed with iron(III) at acidic pH and when LDL oxidation was initiated by azo-compound generated peroxyl radicals. At pH 7.4 histidine is able to prevent LDL oxidation by copper(II) in a thiol mixture similar to the one found in human plasma if present in tenfold excess over homocysteine, but loses its inhibitory effect at higher homocysteine concentrations. The synergistic effect on metal-catalyzed LDL oxidation observed with mixtures of homocysteine and cystine or cysteine sustains the hypothesis that the epidemiological association between raised homocysteine levels and risk of cardiovascular disease is caused by an increase in oxidative stress.

      Keywords

      Abbreviations:

      AAPH, 2,2′-azobis(2-amidinopropane) hydrochloride (), CD, conjugated dienes (), MDA, malondialdehyde (), TBARS, thiobarbituric acid reactive substances ()
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Durand P.
        • Prost M.
        • Loreau N.
        • Lussier Cacan S.
        • Blache D.
        Impaired homocysteine metabolism and atherothrombotic disease.
        Lab. Invest. 2001; 81: 645-672
        • Ueland P.M.
        • Refsum H.
        Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy.
        J. Lab. Clin. Med. 1989; 114: 473-501
        • McCully K.S.
        Homocysteine and vascular disease.
        Nat. Med. 1996; 2: 386-389
        • Welch G.N.
        • Loscalzo J.
        Homocysteine and atherothrombosis.
        N. Engl. J. Med. 1998; 338: 1042-1050
        • Refsum H.
        • Ueland P.M.
        • Nygard O.
        • Vollset S.E.
        Homocysteine and cardiovascular disease.
        Annu. Rev. Med. 1998; 4: 931-962
        • Ueland P.M.
        • Mansoor M.A.
        • Guttormsen A.B.
        • Muller F.
        • Aukrust P.
        • Refsum H.
        • Svardal A.M.
        Reduced, oxidized and protein-bound forms of homocysteine and other aminothiols in plasma comprise the redox thiol status—a possible element of the extracellular antioxidant defense system.
        J. Nutr. 1996; 126: 1281s-1284s
        • Koch H.G.
        • Goebeler M.
        • Marquardt T.
        • Roth J.
        • Harms E.
        The redox status of aminothiols as a clue to homocysteine-induced vascular damage?.
        Eur. J. Pediatr. 1998; 157: 2s102-2s106
        • Thambyrajah J.
        • Townend J.N.
        Homocysteine and atherothrombosis—mechanisms for injury.
        Eur. Heart J. 2000; 21: 967-974
        • Misra H.P.
        Generation of superoxide free radical during the autoxidation of thiols.
        J. Biol. Chem. 1974; 249: 2151-2155
        • Albro P.W.
        • Corbett J.T.
        • Schroeder J.L.
        Generation of hydrogen peroxide by incidental metal ion-catalyzed autooxidation of glutathione.
        J. Inorg. Biochem. 1986; 27: 191-203
        • Dudman N.P.
        • Hicks C.
        • Wang J.
        • Wilcken D.E.
        Human arterial endothelial cell detachment in vitro: its promotion by homocysteine and cysteine.
        Atherosclerosis. 1991; 91: 77-83
        • Jacob N.
        • Bruckert E.
        • Giral P.
        • Foglietti M.J.
        • Turpin G.
        Cysteine is a cardiovascular risk factor in hyperlipidemic patients.
        Atherosclerosis. 1999; 146: 53-59
        • Chisolm G.M.
        • Steinberg D.
        The oxidative modification hypothesis of atherogenesis: an overview.
        Free Radic. Biol. Med. 2000; 28: 1815-1826
        • Mukhopadhyay C.K.
        • Ehrenwald E.
        • Fox P.L.
        Ceruloplasmin enhances smooth muscle cell- and endothelial cell-mediated low density lipoprotein oxidation by a superoxide-dependent mechanism.
        J. Biol. Chem. 1996; 271: 14773-14778
        • Biemond P.
        • van Eijk H.G.
        • Swaak A.J.
        • Koster J.F.
        • Ehrenwald E.
        • Fox P.L.
        Iron mobilization from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes. Possible mechanism in inflammation diseases. Role of endogenous ceruloplasmin in low density lipoprotein oxidation by human U937 monocytic cells.
        J. Clin. Invest. 1984; 73: 1576-1579
        • Abdalla D.S.
        • Campa A.
        • Monteiro H.P.
        Low density lipoprotein oxidation by stimulated neutrophils and ferritin.
        Atherosclerosis. 1992; 97: 149-159
        • Reif D.W.
        Ferritin as a source of iron for oxidative damage.
        Free Radic. Biol. Med. 1992; 12: 417-427
        • Paul T.
        Effect of a prolonged superoxide flux on transferrin and ferritin.
        Arch. Biochem. Biophys. 2000; 382: 253-261
        • Camejo G.
        • Halberg C.
        • Manschik Lundin A.
        • et al.
        Hemin binding and oxidation of lipoproteins in serum: mechanisms and effect on the interaction of LDL with human macrophages.
        J. Lipid Res. 1998; 39: 755-766
        • Silver I.A.
        • Murrills R.J.
        • Etherington D.J.
        Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts.
        Exp. Cell Res. 1988; 175: 266-276
        • Leake D.S.
        Does an acidic pH explain why low density lipoprotein is oxidised in atherosclerotic lesions?.
        Atherosclerosis. 1997; 129: 149-157
        • Welch S.
        A comparison of the structure and properties of serum transferrin from 17 animal species.
        Comp. Biochem. Physiol. B. 1990; 97: 417-427
        • Sipe D.M.
        • Murphy R.F.
        Binding to cellular receptors results in increased iron release from transferrin at mildly acidic pH.
        J. Biol. Chem. 1991; 266: 8002-8007
        • Lamb D.J.
        • Leake D.S.
        Iron released from transferrin at acidic pH can catalyse the oxidation of low density lipoprotein.
        FEBS Lett. 1994; 352: 15-18
        • Fox P.L.
        • Mazumder B.
        • Ehrenwald E.
        • Mukhopadhyay C.K.
        Ceruloplasmin and cardiovascular disease.
        Free Radic. Biol. Med. 2000; 28: 1735-1744
        • Hirano K.
        • Ogihara T.
        • Miki M.
        • Yasuda H.
        • Tamai H.
        • Kawamura N.
        • Mino M.
        Homocysteine induces iron-catalyzed lipid peroxidation of low-density lipoprotein that is prevented by alpha-tocopherol.
        Free Radic. Res. 1994; 21: 267-276
        • Wood J.L.
        • Graham A.
        Structural requirements for oxidation of low-density lipoprotein by thiols.
        FEBS Lett. 1995; 366: 75-80
        • Lynch S.M.
        • Frei B.
        Physiological thiol compounds exert pro- and anti-oxidant effects, respectively, on iron- and copper-dependent oxidation of human low-density lipoprotein.
        Biochim. Biophys. Acta. 1997; 1345: 215-221
        • Heinecke J.W.
        • Kawamura M.
        • Suzuki L.
        • Chait A.
        Oxidation of low density lipoprotein by thiols: superoxide-dependent and -independent mechanisms.
        J. Lipid Res. 1993; 34: 2051-2061
        • Graham A.
        Cellular thiol production and oxidation of low-density lipoprotein.
        Free Radic. Res. 1998; 28: 611-621
        • Burkitt M.J.
        A critical overview of the chemistry of copper-dependent low density lipoprotein oxidation: roles of lipid hydroperoxides, alpha-tocopherol, thiols, and ceruloplasmin.
        Arch. Biochem. Biophys. 2001; 394: 117-135
        • Hogg N.
        The effect of cyst(e)ine on the auto-oxidation of homocysteine.
        Free Radic. Biol. Med. 1999; 27: 28-33
        • Havel R.J.
        • Eder H.A.B.J.H.
        The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum.
        J. Clin. Invest. 1955; 34: 1345-1353
        • Bradford M.M.
        A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
        Anal. Biochem. 1976; 7: 72248-72254
        • Brenner A.J.
        • Harris E.D.
        A quantitative test for copper using bicinchoninic acid.
        Anal. Biochem. 1995; 226: 80-84
        • Mihara M.
        • Uchiyama M.
        Determination of malonaldehyde precursor in tissues by thiobarbituric acid test.
        Anal. Biochem. 1978; 86: 271-278
        • Noble R.P.
        Electrophoretic separation of plasma lipoproteins in agarose gels.
        J. Lipid Res. 1968; 9: 693-700
        • el Saadani M.
        • Esterbauer H.
        • el Sayed M.
        • Goher M.
        • Nassar A.Y.
        • Jurgens G.
        A spectrophotometric assay for lipid peroxides in serum lipoproteins using a commercially available reagent.
        J. Lipid Res. 1989; 30: 627-630
        • Ellman G.
        • Lysko H.
        A precise method for the determination of whole blood and plasma sulfhydryl groups.
        Anal. Biochem. 1979; 93: 98-102
        • Lentner C.
        Physical Chemistry, Composition of the Blood, Haematology, Sonatometric Data. Geigy Scientific Tables. 3. Ciba Geigy, Basel1984
        • Kuzuya M.
        • Yamada K.
        • Hayashi T.
        • Funaki C.
        • Naito M.
        • Asai K.
        • Kuzuya F.
        Role of lipoprotein-copper complex in copper catalyzed-peroxidation of low-density lipoprotein.
        Biochim. Biophys. Acta. 1992; 1123: 334-341
        • Ueda J.
        • Shimazu Y.
        • Ozawa T.
        Reactions of copper(II)-oligopeptide complexes with hydrogen peroxide: effects of biological reductants.
        Free Radic. Biol. Med. 1995; 18: 929-933
        • Bedwell S.
        • Dean R.T.
        • Jessup W.
        The action of defined oxygen-centred free radicals on human low-density lipoprotein.
        Biochem. J. 1989; 262: 707-712
        • Winkler P.
        • Schaur R.J.
        • Schauenstein E.
        Selective promotion of ferrous ion-dependent lipid peroxidation in Ehrlich ascites tumor cells by histidine as compared with other amino acids.
        Biochim. Biophys. Acta. 1984; 796: 226-231
        • Patterson R.A.
        • Leake D.S.
        Human serum, cysteine and histidine inhibit the oxidation of low density lipoprotein less at acidic pH.
        FEBS Lett. 1998; 434: 317-321
        • Halvorsen B.
        • Brude I.
        • Drevon C.A.
        • Nysom J.
        • Ose L.
        • Christiansen E.N.
        • Nenseter M.S.
        Effect of homocysteine on copper ion-catalyzed, azo compound-initiated, and mononuclear cell-mediated oxidative modification of low density lipoprotein.
        J. Lipid Res. 1996; 37: 1591-1600