Keiko Tanaka*, Mikiko Yasuhara, Kuniharu Suzumura, Hiroshi Narita and Toshikazu Suzuki
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan
*Corresponding author. FAX: +81-48-433-8158, E-mail: keiko-t@tanabe.co.jp
Abstract: We investigated effects of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and its major metabolites, M2 and M4, on CuSO4-induced low-density lipoprotein (LDL) oxidation and cholesteryl ester accumulation in mouse peritoneal macrophages. All the test compounds inhibited LDL oxidation, and M2 had the most potent effect comparable to vitamin E. When LDL was previously incubated with the test compounds in the presence of CuSO4, the pre-treatment resulted in a marked reduction of facilitated cholesteryl ester accumulation in macrophages. Supplementation of mevalonate did not overcome the inhibitory effects of fluvastatin and its metabolites on both LDL oxidation and facilitated cholesterol esterification. Pravastatin, another HMG-CoA reductase inhibitor, did not show any inhibitory effect. Consequently, these effects of fluvastatin and its metabolites are considered to be derived from their own unique chemical structures. Moreover, fluvastatin and M2 directly inhibited cholesterol esterification induced by oxidized LDL in macrophages, but pravastatin was also found to have a weak effect. As their inhibitory effects were overcome by addition of mevalonate, the direct inhibitory effect on cholesterol esterification would be a common property of HMG-CoA reductase inhibitors. The inhibitory effects of fluvastatin and its metabolites on both LDL oxidation and cholesterol esterification in macrophages may contribute to the antiatherogenic action in vivo.
Keywords: HMG-CoA reductase, Macrophage, Oxidized low-density lipoprotein, Cholesteryl ester, Antioxidant
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