PMID- 15734902
OWN - NLM
STAT- MEDLINE
DCOM- 20050705
LR  - 20181201
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 313
IP  - 2
DP  - 2005 May
TI  - Cilostazol reduces atherosclerosis by inhibition of superoxide and tumor necrosis 
      factor-alpha formation in low-density lipoprotein receptor-null mice fed high 
      cholesterol.
PG  - 502-9
AB  - 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.
FAU - Lee, Jeong Hyun
AU  - Lee JH
AD  - Department of Pharmacology, College of Medicine, Pusan National University, 
      Busan, Korea.
FAU - Oh, Goo Taeg
AU  - Oh GT
FAU - Park, So Youn
AU  - Park SY
FAU - Choi, Jae-Hoon
AU  - Choi JH
FAU - Park, Jong-Gil
AU  - Park JG
FAU - Kim, Chi Dae
AU  - Kim CD
FAU - Lee, Won Suk
AU  - Lee WS
FAU - Rhim, Byung Yong
AU  - Rhim BY
FAU - Shin, Yung Woo
AU  - Shin YW
FAU - Hong, Ki Whan
AU  - Hong KW
LA  - eng
PT  - Comparative Study
PT  - Journal Article
DEP - 20050225
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Cholesterol, Dietary)
RN  - 0 (Receptors, LDL)
RN  - 0 (Tetrazoles)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 11062-77-4 (Superoxides)
RN  - N7Z035406B (Cilostazol)
SB  - IM
MH  - Animals
MH  - Arteriosclerosis/chemically induced/*drug therapy/metabolism
MH  - Cell Line
MH  - Cholesterol, Dietary/toxicity
MH  - Cilostazol
MH  - *Diet, Atherogenic
MH  - Dose-Response Relationship, Drug
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Receptors, LDL/*deficiency/genetics
MH  - Superoxides/*antagonists & inhibitors/metabolism
MH  - Tetrazoles/pharmacology/*therapeutic use
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/biosynthesis
EDAT- 2005/03/01 09:00
MHDA- 2005/07/06 09:00
CRDT- 2005/03/01 09:00
PHST- 2005/03/01 09:00 [pubmed]
PHST- 2005/07/06 09:00 [medline]
PHST- 2005/03/01 09:00 [entrez]
AID - jpet.104.079780 [pii]
AID - 10.1124/jpet.104.079780 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2005 May;313(2):502-9. doi: 10.1124/jpet.104.079780. Epub 
      2005 Feb 25.