Abstract
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-α (TNF-α) production were significantly lowered by cilostazol in situ as well as in cultured human umbilical vein endothelial cells (HUVECs). TNF-α-induced increased inhibitory κBα degradation in the cytoplasm and nuclear factor-κB (NF-κB) 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-κB activation and p65 translocation into the nuclei. Furthermore, in gel shift and DNA-binding assay, cilostazol inhibited NF-κB/DNA complex and nuclear DNA-binding activity of the NF-κB 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-α formation, and thereby reducing NF-κB activation/transcription, VCAM-1/MCP-1 expressions, and monocyte recruitments.
Footnotes
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Jeong Hyun Lee and Goo Taeg Oh equally contributed to this study.
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doi:10.1124/jpet.104.079780.
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ABBREVIATIONS: VCAM-1, vascular cell adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; TNF-α, tumor necrosis factor-α; NF-κB, nuclear factor-κB; IκBα, inhibitory κBα; Ldlr, low-density lipoprotein receptor; HDL, high-density lipoprotein; RLP, remnant lipoprotein particles; cilostazol, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3,4-dihydro-2(1H)-quinolinone; HUVEC, human umbilical vein endothelial cell; ELISA, enzyme-linked immunosorbent assay; BAY 11-7085, (E)-3[(4-t-butylphenyl)sulfonyl]-2-propenenitrile.
- Received October 25, 2004.
- Accepted February 15, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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