THE ANTIOXIDANT EFFECT OF SPERMINE NONOATE IN HUMAN LOW-DENSITY-LIPOPROTEIN

被引:53
作者
GOSS, SPA [1 ]
HOGG, N [1 ]
KALYANARAMAN, B [1 ]
机构
[1] MED COLL WISCONSIN, BIOPHYS RES INST, MILWAUKEE, WI 53226 USA
关键词
D O I
10.1021/tx00047a021
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The nitric oxide ((NO)-N-.) donor N-[4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino]butyl]-1,3-propanediamine, also referred to as Spermine NONOate (SNN), inhibited the copper(II) sulfate-initiated oxidative modification of human low-density lipoprotein (LDL) as measured by the formation of thiobarbituric acid reactive substances, conjugated diene formation, and changes in electrophoretic mobility. The presence of the nitronyl nitroxide 1-oxy-2-[p-(trimethylammoniumyl)phenyl]-4,4,5,5-tetramethylimadazoline 3-oxide, a scavenger of (NO)-N-., antagonized the inhibitory activity of SNN. The inhibition of copper-dependent LDL oxidation had a nonlinear dependence on SNN concentration. Low concentrations of SNN (<4 mu M) were only poorly effective at inhibiting LDL oxidation; however, a dramatic enhancement of inhibition occurred above 4 mu M SNN. This behavior was qualitatively different from that of butylated hydroxytoluene, a phenolic chain-breaking antioxidant, which exhibited an approximately linear concentration dependence in this system. Addition of 13[S-(E,Z)]-hydroperoxy-9,11-octadecadienoic acid, a lipid hydroperoxide, to LDL diminished the antioxidant effect of 4 and 8 mu M SNN, but not that of 12 mu M SNN. SNN inhibited the depletion of alpha-tocopherol during both copper-dependent and 2,2'-azobis(2-amidinopropane)-dependent oxidation of LDL. We propose that a direct reaction is occurring between (NO)-N-. and the lipid peroxyl radical, forming a lipid-nitroso adduct. Formation of this product would not only remove the lipid peroxyl radical, thus preventing chain propagation, but would also prohibit the regeneration of lipid hydroperoxide, thereby stopping further transition metal ion-dependent initiation. The difference in the kinetic behavior between SNN and conventional antioxidants can be explained by this effect.
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页码:800 / 806
页数:7
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共 41 条
  • [1] APPARENT HYDROXYL RADICAL PRODUCTION BY PEROXYNITRITE - IMPLICATIONS FOR ENDOTHELIAL INJURY FROM NITRIC-OXIDE AND SUPEROXIDE
    BECKMAN, JS
    BECKMAN, TW
    CHEN, J
    MARSHALL, PA
    FREEMAN, BA
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1990, 87 (04) : 1620 - 1624
  • [2] CHRONIC INHIBITION OF NITRIC-OXIDE PRODUCTION ACCELERATES NEOINTIMA FORMATION AND IMPAIRS ENDOTHELIAL FUNCTION IN HYPERCHOLESTEROLEMIC RABBITS
    CAYATTE, AJ
    PALACINO, JJ
    HORTEN, K
    COHEN, RA
    [J]. ARTERIOSCLEROSIS AND THROMBOSIS, 1994, 14 (05): : 753 - 759
  • [3] OXIDATION OF LDL TO A BIOLOGICALLY-ACTIVE FORM BY DERIVATIVES OF NITRIC-OXIDE AND NITRITE IN THE ABSENCE OF SUPEROXIDE - DEPENDENCE ON PH AND OXYGEN
    CHANG, GJ
    WOO, P
    HONDA, HM
    IGNARRO, LJ
    YOUNG, L
    BERLINER, JA
    DEMER, LL
    [J]. ARTERIOSCLEROSIS AND THROMBOSIS, 1994, 14 (11): : 1808 - 1814
  • [4] ANTIATHEROGENIC EFFECTS OF L-ARGININE IN THE HYPERCHOLESTEROLEMIC RABBIT
    COOKE, JP
    SINGER, AH
    TSAO, P
    ZERA, P
    ROWAN, RA
    BILLINGHAM, ME
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1992, 90 (03) : 1168 - 1172
  • [5] THE SIMULTANEOUS GENERATION OF SUPEROXIDE AND NITRIC-OXIDE CAN INITIATE LIPID-PEROXIDATION IN HUMAN LOW-DENSITY-LIPOPROTEIN
    DARLEYUSMAR, VM
    HOGG, N
    OLEARY, VJ
    WILSON, MT
    MONCADA, S
    [J]. FREE RADICAL RESEARCH COMMUNICATIONS, 1992, 17 (01): : 9 - 20
  • [6] LOSS OF ALPHA-TOCOPHEROL UPON EXPOSURE TO NITRIC-OXIDE OR THE SYDNONIMINE SIN-1
    DEGROOT, H
    HEGI, U
    SIES, H
    [J]. FEBS LETTERS, 1993, 315 (02) : 139 - 142
  • [7] CORRECTION OF ENDOTHELIAL DYSFUNCTION IN CORONARY MICROCIRCULATION OF HYPERCHOLESTEROLEMIC PATIENTS BY L-ARGININE
    DREXLER, H
    ZEIHER, AM
    MEINZER, K
    JUST, H
    [J]. LANCET, 1991, 338 (8782-3) : 1546 - 1550
  • [8] THE ROLE OF LIPID-PEROXIDATION AND ANTIOXIDANTS IN OXIDATIVE MODIFICATION OF LDL
    ESTERBAUER, H
    GEBICKI, J
    PUHL, H
    JURGENS, G
    [J]. FREE RADICAL BIOLOGY AND MEDICINE, 1992, 13 (04) : 341 - 390
  • [9] CONTINUOUS MONITORING OF INVITRO OXIDATION OF HUMAN LOW-DENSITY LIPOPROTEIN
    ESTERBAUER, H
    STRIEGL, G
    PUHL, H
    ROTHENEDER, M
    [J]. FREE RADICAL RESEARCH COMMUNICATIONS, 1989, 6 (01): : 67 - 75
  • [10] OXYGEN RADICAL CHEMISTRY OF POLY-UNSATURATED FATTY-ACIDS
    GARDNER, HW
    [J]. FREE RADICAL BIOLOGY AND MEDICINE, 1989, 7 (01) : 65 - 86