Received for publication October 26, 2004.
Revised February 14, 2005.
Accepted for publication February 15, 2005.

Cilostazol Reduces Atherosclerosis by Inhibition of Superoxide and TNF- Formation in Low-density Lipoprotein Receptor-null Mice fed High Cholesterol

Abstract

This study shows that cilostazol suppresses the atherosclerotic lesion formation in the low density lipoprotein receptor (Ldlr)-null mice. Ldlr-null mice fed 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), 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 TNF- production were significantly lowered by cilostazol in situ as well as in cultured HUVECs. TNF--induced increased inhibitory kappa B (IB) degradation in the cytoplasm and nuclear factor-kappa B (NF-B) p65 activation in the nuclei of HUVECs were reversed by cilostazol (1 ~100 µM) as well as by BAY 11-7085 (10 µM), suggesting that cilostazol strongly inhibits NF-B activation and p65 translocation into the nuclei. Further, 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.

Key words: Cilostazol, LDL receptor-null mice, MCP-1, NF-B, TNF-, VCAM-1

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