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CARDIOVASCULAR

Cilostazol Reduces Atherosclerosis by Inhibition of Superoxide and Tumor Necrosis Factor- Formation in Low-Density Lipoprotein Receptor-Null Mice Fed High Cholesterol

Department of Pharmacology (J.H.L., S.Y.P., C.D.K., W.S.L., B.Y.R., K.W.H.) and Internal Medicine (Y.W.S.), College of Medicine, Pusan National University, Busan, Korea; and Division of Molecular Life Sciences, Ewha Womans University, Seoul, Korea (G.T.O., J.-H.C., J.-G.P.)

This study shows that 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H)-quinolinone (cilostazol) suppresses the atherosclerotic lesion formation in the low-density lipoprotein receptor (Ldlr)-null mice. Ldlr-null mice fed a high cholesterol diet showed multiple plaque lesions in the proximal ascending aorta including aortic sinus, accompanied by increased macrophage accumulation with increased expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). Supplementation of cilostazol (0.2% w/w) in diet significantly decreased the plaque lesions with reduced macrophage accumulation and suppression of VCAM-1 and MCP-1 in situ. Increased superoxide and tumor necrosis factor- (TNF-) production were significantly lowered by cilostazol in situ as well as in cultured human umbilical vein endothelial cells (HUVECs). TNF--induced increased inhibitory B degradation in the cytoplasm and nuclear factor-B (NF-B) p65 activation in the nuclei of HUVECs were reversed by cilostazol (1 100 µM) as well as by (E)-3[(4-t-butylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7085) (10 µM), suggesting that cilostazol strongly inhibits NF-B activation and p65 translocation into the nuclei. Furthermore, in gel shift and DNA-binding assay, cilostazol inhibited NF-B/DNA complex and nuclear DNA-binding activity of the NF-B in the nuclear extracts of the RAW 264.7 cells. Taken together, it is suggested that the anti-atherogenic effect of cilostazol in cholesterol-fed Ldlr-null mice is ascribed to its property to suppress superoxide and TNF- formation, and thereby reducing NF-B activation/transcription, VCAM-1/MCP-1 expressions, and monocyte recruitments.

Address correspondence to: Dr. Ki Whan Hong, Department of Pharmacology, College of Medicine, Pusan National University, Ami-Dong 1-Ga, Seo-Gu, Busan 602-739, Korea. E-mail: kwhong{at}pusan.ac.kr

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