Functional evidence for anti-oxidant action of fluvastatin on low-density lipoprotein using isolated macrophages and aorta.
1. Fluvastatin has been reported to have not only a hypocholesterolaemic effect, but also a protective effect on low-density lipoprotein (LDL) from oxidation. We functionally evaluated the anti-oxidant effect of fluvastatin on oxidation of LDL by copper ions in vitro using mouse macrophages and rabbit aorta preparations. 2. After native LDL (N-LDL) from rabbit plasma had been pre-incubated in the presence or absence of fluvastatin (10 micromol/L) for 4 h, the N-LDL was mildly oxidized by incubation with 5 micromol/L CuCl2 for 5 h and two oxidized LDL, fluvastatin-pretreated (Flu-OxLDL) and -non-treated (OxLDL), were prepared. The level of thiobarbituric acid-reactive substances (TBARS) in Flu-OxLDL and OxLDL markedly increased compared with N-LDL. The degree of increment was significantly less in Flu-OxLDL than OxLDL. 3. When macrophages were incubated with Flu-OxLDL or OxLDL, the amount of cholesteryl ester that accumulated in the macrophages markedly increased compared with N-LDL. The degree of increment was significantly less in Flu-OxLDL than OxLDL. 4. Acetylcholine-induced endothelium-dependent relaxations in rabbit aortic rings were impaired in the presence of either Flu-OxLDL or OxLDL. The degree of impairment was significantly less in Flu-OxLDL. 5. The increased TBARS level, facilitated cholesteryl ester accumulation in macrophages and impaired endothelium-dependent relaxation elicited by OxLDL were not affected by simultaneous treatment with fluvastatin (10 micromol/L). 6. These findings indicate that fluvastatin can protect plasma LDL from oxidative modification and, thereby, prevent cholesterol accumulation in macrophages and endothelial dysfunction in blood vessels. This additional anti-oxidative effect of fluvastatin may be beneficial for preventing the progression of atherosclerosis.
Kagota
S
S
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan. skagota@mwu.mukogawa-u.ac.jp
Yamaguchi
Y
Y
Nakamura
K
K
Kunitomo
M
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002788:Cholesterol Esters / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D007211:Indoles / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000187:drug effects* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D011817:Rabbits
D000924:Anticholesteremic Agents; D000975:Antioxidants; D002788:Cholesterol Esters; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D008077:Lipoproteins, LDL; D000077340:Fluvastatin