Skip Navigation


Cardiovascular Research Advance Access originally published online on August 14, 2008
Cardiovascular Research 2009 81(1):133-139; doi:10.1093/cvr/cvn226
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow All Versions of this Article:
81/1/133    most recent
cvn226v2
cvn226v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hattori, Y.
Right arrow Articles by Kasai, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hattori, Y.
Right arrow Articles by Kasai, K.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

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 nuclear factor-{kappa}B activation via AMP-activated protein kinase 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 86 4632. E-mail address: yhattori{at}dokkyomed.ac.jp

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)-{kappa}B activation by activating AMP-activated protein kinase (AMPK) in vascular endothelial cells.

Methods and results: 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 (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 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-{kappa}B activation by TNF{alpha}.

Conclusion: In the 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; Cyclic AMP

Time for primary review: 29 days


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Circ. Res.Home page
B. Fisslthaler and I. Fleming
Activation and Signaling by the AMP-Activated Protein Kinase in Endothelial Cells
Circ. Res., July 17, 2009; 105(2): 114 - 127.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.