Published Online
on April 24, 2006

A more recent version of this article appeared on June 1, 2006

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Submitted on February 21, 2006
Revised on March 11, 2006

Metformin Inhibits Cytokine-Induced Nuclear Factor B Activation Via AMP-Activated Protein Kinase Activation in Vascular Endothelial Cells

Yoshiyuki Hattori^*; Kunihiro Suzuki; Sachiko Hattori; and Kikuo Kasai

From the Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.

^* To whom correspondence should be addressed. E-mail: yhattori{at}dokkyomed.ac.jp.

Abstract--AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in regulation of energy homeostasis and metabolic stress. Metformin has been shown to activate AMPK. We hypothesized that metformin may prevent nuclear factor B (NF-B) activation in endothelial cells exposed to inflammatory cytokines. Metformin was observed to activate AMPK, as well as its downstream target, phosphoacetyl coenzyme A carboxylase, in human umbilical vein endothelial cells (HUVECs). Metformin also dose-dependently inhibited tumor necrosis factor (TNF)--induced NF-B activation and TNF--induced IB kinase activity. Furthermore, metformin attenuated the TNF--induced gene expression of various proinflammatory and cell adhesion molecules, such as vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1, in HUVECs. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR), dose-dependently inhibited TNF-- and interleukin-1-induced NF-B reporter gene expression. AICAR also suppressed the TNF-- and interleukin-1-induced gene expression of vascular cell adhesion molecule-1, E-selectin, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 in HUVECs. The small interfering RNA for AMPK1 attenuated metformin or AICAR-induced inhibition of NF-B activation by TNF-, suggesting a possible role of AMPK in the regulation of cell inflammation. In light of these findings, we suggest that metformin attenuates the cytokine-induced expression of proinflammatory and adhesion molecule genes by inhibiting NF-B activation via AMPK activation. Thus, it might be useful to target AMPK signaling in future efforts to prevent atherogenic and inflammatory vascular disease.

Key words: endothelium • cell adhesion molecules • diabetes mellitus

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