Cilostazol, a cAMP phosphodiesterase inhibitor, attenuates the production of monocyte chemoattractant protein-1 in response to tumor necrosis factor-alpha in vascular endothelial cells.
The induction of monocyte chemoattractant protein-1 (MCP-1) in vascular endothelial cells is thought to be an initial event in the development of atherosclerotic lesions. Therefore, inhibition of MCP-1 production may exhibit some effects in preventing atherosclerosis. In the present study, we found that 10 microM cilostazol, a cAMP phosphodiesterase inhibitor, increased the intracellular cAMP content by a twenty-five times of the basal level and resulted in the reduction of basal MCP-1 release by 41% from 168 +/- 11 ng/24 hr/mg protein to 99 +/- 14 ng/24 hr/mg protein (P < 0.001) from cultured human umbilical vein endothelial cells. Furthermore, 10 microM cilostazol also significantly attenuated the dose-dependent increment of MCP-1 production by tumor necrosis factor-alpha. The inhibition was consistent with the reduction of MCP-1 mRNA level, possibly through reduced activation of transcription factor NF-kappa B level. Similarly, 1 mM dibutyryl cAMP inhibited MCP-1 production in endothelial cells. These data suggest that cilostazol inhibits MCP-1 production through increased intracellular cAMP levels and modulation of its expression in vascular endothelial cells.
Nishio
Y
Y
Third Department of Medicine, Shiga University of Medical Science, Japan.
Kashiwagi
A
A
Takahara
N
N
Hidaka
H
H
Kikkawa
R
R
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077407:Cilostazol; D000242:Cyclic AMP / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D018932:Chemokine CCL2; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D003994:Bucladesine; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000077407:Cilostazol