INHIBITION OF THE OXIDATIVE MODIFICATION OF LDL BY NITECAPONE

被引：24

作者：

PENTIKAINEN, MO ^{[1
]}

LINDSTEDT, KA ^{[1
]}

KOVANEN, PT ^{[1
]}

机构：

[1] WIHURI RES INST,SF-00140 HELSINKI,FINLAND

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 1995年 / 15卷 / 06期

关键词：

NITECAPONE; LDL; LIPID PEROXIDATION; ATHEROSCLEROSIS; MACROPHAGES;

D O I：

10.1161/01.ATV.15.6.740

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

We studied in vitro the ability of nitecapone, 3-[(3,4-dihydroxy-5-nitrophenyl)methylene]-2,4-pentanedione, a novel water-soluble compound with antioxidative properties, to inhibit the LDL oxidation promoted by copper ions, the aqueous free radical generator 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH), and mouse peritoneal macrophages. In these three oxidation systems, the extent of LDL oxidation was determined by measuring the formation of conjugated dienes, the formation of thiobarbituric acid-reactive substances, the change in the electrophoretic mobility of LDL, and the uptake of LDL by macrophages. When LDL oxidation was promoted by copper ions, the reaction was found to be inhibited by nitecapone added in a three- to five-molar excess of the concentration of copper ions. The mechanism by which nitecapone exerted its antioxidative effect in copper-mediated LDL oxidation depended on binding and redox inactivation of the copper ions. Moreover, nitecapone released LDL-bound copper ions and so rendered the LDL particles more resistant to oxidation. In contrast to a water-soluble alpha-tocopherol analogue that was rapidly consumed during the oxidative process, nitecapone retained its inhibitory effect for at least 2 days. Using immobilized metal ion affinity chromatography, we showed that nitecapone binds both copper and iron ions, whereas its affinity for zinc ions is low. Nitecapone also inhibited LDL oxidation in the free radical-mediated oxidation system (AAPH). In this system, nitecapone showed synergistic antioxidative action with ascorbic acid. Finally, nitecapone inhibited macrophage-mediated LDL oxidation. Accordingly, nitecapone appears to have a unique antioxidative profile in that it both selectively chelates pro-oxidative transition metals and scavenges free radicals. Moreover, nitecapone has the potential of protecting LDL from oxidation in more complex biological in vitro systems in which multiple modes of oxidative stress act simultaneously, suggesting that this new compound, already tested in humans for its ability to inhibit catechol-O-methyltransferase activity, could potentially be used as an antioxidant drug.

引用

页码：740 / 747

页数：8

共 63 条

[1]

Steinberg D., Parthasarathy S., Carew T.E., Khoo J.C., Witztum J.L., Beyond cholesterol: Modifications of low-density lipoprotein that increase its atherogenicity, N Engl J Med, 320, pp. 915-924, (1989)

[2]

Henriksen T., Mahoney E.M., Steinberg D., Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: Recognition by receptors for acetylated low density lipoproteins, Proc Natl Acad Sci U S A, 78, pp. 6499-6503, (1981)

[3]

Parthasarathy S., Printz D.J., Boyd D., Joy L., Steinberg D., Macrophage oxidation of low-density lipoprotein generates a modified form recognized by the scavenger receptor, Arteriosclerosis, 6, pp. 505-510, (1986)

[4]

Brown M.S., Goldstein J.L., Lipoprotein metabolism in the macrophage: Implications for cholesterol deposition in atherosclerosis, Annu Rev Biochem, 52, pp. 223-261, (1983)

[5]

Henriksen T., Mahoney E.M., Steinberg D., Enhanced macrophage degradation of biologically modified low-density lipoprotein, Arteriosclerosis, 3, pp. 149-159, (1983)

[6]

Lamb D.J., Wilkins G.M., Leake D.S., The oxidative modification of low density lipoprotein by human lymphocytes, Atherosclerosis, 92, pp. 187-192, (1992)

[7]

Steinbrecher U.P., Parthasarathy S., Leake D.S., Witztum J.L., Steinberg D., Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids, Proc Natl Acad Sci U S A, 81, pp. 3883-3887, (1984)

[8]

Lynch S.M., Frei B., Mechanisms of copper- and iron-dependent oxidative modification of human low density lipoprotein, J Lipid Res, 34, pp. 1745-1753, (1993)

[9]

Niki E., Free radical initiators as a source of water- Or lipid-soluble peroxyl radicals, Methods Enzymol, 187, pp. 100-108, (1990)

[10]

Esterbauer H., Striegl G., Buhl H., Rootheneder M., Continuous monitoring of in vitro oxidation of human low density lipoprotein, Free Radic Res Commun, 6, pp. 67-75, (1990)

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