title: Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis factor-alpha formation in low-density lipoprotein receptor-null mice fed high cholesterol.
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-alpha (TNF-alpha) production were significantly lowered by cilostazol in situ as well as in cultured human umbilical vein endothelial cells (HUVECs). TNF-alpha-induced increased inhibitory kappaBalpha degradation in the cytoplasm and nuclear factor-kappaB (NF-kappaB) p65 activation in the nuclei of HUVECs were reversed by cilostazol (1 approximately 100 microM) as well as by (E)-3[(4-t-butylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7085) (10 microM), suggesting that cilostazol strongly inhibits NF-kappaB activation and p65 translocation into the nuclei. Furthermore, in gel shift and DNA-binding assay, cilostazol inhibited NF-kappaB/DNA complex and nuclear DNA-binding activity of the NF-kappaB 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-alpha formation, and thereby reducing NF-kappaB activation/transcription, VCAM-1/MCP-1 expressions, and monocyte recruitments.
authors.affiliation: Department of Pharmacology, College of Medicine, Pusan National University, Busan, Korea.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Choi
authors.forename: Jong-Gil
authors.initials: JG
authors.lastname: Park
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
authors.forename: Won Suk
authors.initials: WS
authors.lastname: Lee
authors.forename: Byung Yong
authors.initials: BY
authors.lastname: Rhim
authors.forename: Yung Woo
authors.initials: YW
authors.lastname: Shin
authors.forename: Ki Whan
authors.initials: KW
authors.lastname: Hong
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D002791:Cholesterol, Dietary / Q000633:toxicity; D000077407:Cilostazol; D004036:Diet, Atherogenic; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D002791:Cholesterol, Dietary; D011973:Receptors, LDL; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D000077407:Cilostazol