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Cardiovascular Research Advance Access [Accepted Manuscript] published online on August 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn226
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Cilostazol inhibits cytokine-induced NF-{kappa}B activation via AMPK activation in vascular endothelial cells

Yoshiyuki Hattori*, Kunihiro Suzuki, Atsuko Tomizawa, Noriko Hirama, Toshie Okayasu, Sachiko Hattori, Hiroko Satoh, Kazumi Akimoto and Kikuo Kasai

Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan

* Corresponding author. Tel: +81-282-87-2150, fax: +81-282-87-2150 E-mail address: yhattori{at}dokkyomed.ac.jp (Y. Hattori)

Aims: Cilostazol is a selective inhibitor of phosphodiesterase 3 that increases intracellular 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)-{kappa}B activation by activating AMP-activated protein kinase (AMPK) in vascular endothelial cells.

Methods and results: Cilostazol was observed to activate AMPK as well as 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 cyclic AMP analog, pCTP-cAMP, did not induce AMPK phosphorylation and had no effect on cilostazol-induced AMPK phosphorylation, suggesting cilostazol-induced AMPK activation occurs through a signalling pathway independent of cyclic AMP. Cilostazol also dose-dependently inhibited tumor necrosis factor (TNF){alpha}-induced NF-{kappa}B activation and TNF{alpha}-induced I{kappa}B kinase activity. Furthermore, cilostazol attenuated the TNF{alpha}-induced gene expression of various pro-inflammatory and cell adhesion molecules, such as VCAM-1, E-selectin, ICAM-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-{kappa}B activation by TNF{alpha}.

Conclusion: In light of these findings, we suggest that cilostazol might attenuate the cytokine-induced expression of adhesion molecule genes by inhibiting NF-{kappa}B following AMPK activation.

KEYWORDS AMPK; NF-{kappa}B; cilostazol; endothelial cells; cAMP

Time for primary review: 29 Days


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