Inhibitory effect of inducible type nitric oxide synthase on oxidative modification of low density lipoprotein by vascular smooth muscle cells.
Oxidative modification of low density lipoprotein (LDL) plays an important role in atherogenesis. Inducible type nitric oxide synthase (iNOS) has been shown to be expressed in vascular smooth muscle cells (VSMC) of atherosclerotic arteries. Nitric oxide (NO) donors have been shown to inhibit metal ion- or cell-mediated oxidation of LDL. To elucidate whether NO produced by iNOS in VSMC inhibit oxidation of LDL, we investigated the effect of NO donors and iNOS-induction in VSMC on oxidation of LDL. NO donor, S-Nitroso-n-acetylpenicillamine (SNAP) or 3-morpholinosydnonimine (SIN-1) (0.1-1.0 mmol/l) dose-dependently reduced copper-induced oxidation of LDL as demonstrated by the inhibition of electrophoretic mobilities on agarose gels and the formation of thiobarbituric acid-reactive substances (TBARS) and conjugated dienes. Moreover, treatment with IL-1beta (5-50 ng/ml) reduced the increases in electrophoretic mobilities on agarose gels and TBARS formation in association with increases in NO production. In addition, inhibition of NO production by NG-monomethyl-L-arginine monoacetate reduced the inhibitory effect of IL-1beta on LDL oxidation. These results indicate that NO release via iNOS action induced by cytokines in VSMC may play protective roles in oxidative modification of LDL during the atherosclerosis process.
Rikitake
Y
Y
The First Department of Internal Medicine, Kobe University, School of Medicine, Japan.
Hirata
K
K
Kawashima
S
S
Akita
H
H
Yokoyama
M
M
D000818:Animals; D002478:Cells, Cultured; D003300:Copper / Q000494:pharmacology; D004587:Electrophoresis, Agar Gel; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D026423:S-Nitroso-N-Acetylpenicillamine; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C002385:linsidomine; D003300:Copper; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D000254:Sodium-Potassium-Exchanging ATPase; D010396:Penicillamine