Cilostazol inhibits cytokine-induced nuclear factor-kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells.
Cardiovasc Res
; 81(1): 133-9, 2009 Jan 01.
Article
em En
| MEDLINE
| ID: mdl-18703532
ABSTRACT
AIMS:
Cilostazol is a selective inhibitor of phosphodiesterase 3 that increases intracellular cyclic AMP (cAMP) levels and activates protein kinase A, thereby inhibiting platelet aggregation and inducing peripheral vasodilation. We hypothesized that cilostazol may prevent inflammatory cytokine induced-nuclear factor (NF)-kappaB activation by activating AMP-activated protein kinase (AMPK) in vascular endothelial cells. METHODS ANDRESULTS:
Cilostazol was observed to activate AMPK and its downstream target, acetyl-CoA carboxylase, in human umbilical vein endothelial cells (HUVEC). Phosphorylation of AMPK with cilostazol was not affected by co-treatment with an adenylate cyclase inhibitor, SQ 22536, and a cell-permeable cAMP analogue, pCTP-cAMP, did not induce AMPK phosphorylation and had no effect on cilostazol-induced AMPK phosphorylation, suggesting that cilostazol-induced AMPK activation occurs through a signalling pathway independent of cyclic AMP. Cilostazol also dose-dependently inhibited tumour necrosis factor alpha (TNFalpha)-induced NF-kappaB activation and TNFalpha-induced I kappa B kinase activity. Furthermore, cilostazol attenuated the TNFalpha-induced gene expression of various pro-inflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, monocyte chemoattractant protein-1 (MCP-1), and PECAM-1 in HUVEC. RNA interference of AMPK alpha 1 or the AMPK inhibitor compound C attenuated cilostazol-induced inhibition of NF-kappaB activation by TNFalpha.CONCLUSION:
In the light of these findings, we suggest that cilostazol might attenuate the cytokine-induced expression of adhesion molecule genes by inhibiting NF-kappaB following AMPK activation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Fosfodiesterase
/
Proteínas Quinases
/
Tetrazóis
/
Endotélio Vascular
/
NF-kappa B
/
Fator de Necrose Tumoral alfa
Limite:
Humans
Idioma:
En
Revista:
Cardiovasc Res
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Japão