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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2652.)
© 2006 American Heart Association, Inc.

Vascular Biology

Histone Deacetylase Inhibitor Reduces Monocyte Adhesion to Endothelium Through the Suppression of Vascular Cell Adhesion Molecule-1 Expression

Kenji Inoue; Mika Kobayashi; Kiichiro Yano; Mai Miura; Akashi Izumi; Chikage Mataki; Takeshi Doi; Takao Hamakubo; Patrick C. Reid; David A. Hume; Minoru Yoshida; William C. Aird; Tatsuhiko Kodama; Takashi Minami

From Laboratory for Systems Biology and Medicine (K.I., M.K., M.M., A.I., C.M., T.H., P.C.R., T.K., T.M.), Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan; Tokyo Research Laboratories (T.D.), Kowa Company Ltd, Tokyo, Japan; Institute for Molecular Bioscience (D.A.H.), University of Queensland, Brisbane, Australia; Chemical Genetics Laboratory (M.Y.), RIKEN, Saitama, Japan; The Department of Molecular and Vascular Medicine (K.Y., W.C.A.), Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, Mass.

Correspondence to Takashi Minami, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro, Tokyo, 153-8904, Japan. E-mail minami{at}med.rcast.u-tokyo.ac.jp

Objective— Tumor necrosis factor (TNF)- initiates numerous changes in endothelial cell (EC) gene expression that contributes to the pathology of various diseases including inflammation. We hypothesized that TNF-–mediated gene induction involves multiple signaling pathways, and that inhibition of one or more of these pathways may selectively target subsets of TNF-–responsive genes and functions.

Methods and Results— Human umbilical vein endothelial cells (ECs) were preincubated with inhibitors of PI3 kinase (LY294002), histone deacetylases (HDAC) (trichostatin A [TSA]), de novo protein synthesis (CHX), proteasome (MG-132), and GATA factors (K-11430) before exposure to TNF- at 4 hours and analyzed by microarray. TNF-–mediated induction of vascular cell adhesion molecule-1 (VCAM-1) was attenuated by all of these inhibitors, whereas in contrast, stimulation of intercellular adhesion molecule-1 (ICAM-1) was blocked by MG-132 alone. Moreover TSA blocked TNF-–mediated induction of monocyte adhesion both in vitro and in vivo through the suppression of VCAM-1. Further analysis demonstrated that HDAC3 plays a significant role in the regulation of TNF-–mediated VCAM-1 expression.

Conclusions— TNF- activates ECs via multiple signaling pathways, and these pathways may be selectively targeted to modulate EC function. Moreover, TSA treatment reduced monocyte adhesion via VCAM-1 suppression in vitro and in vivo, suggesting that TSA might be useful for the attenuation of the inflammatory response in EC.

A global-survey of TNF--signaling in ECs revealed that VCAM-1 expression is highly induced in a process dependent on PI3-K, GATA, HDAC, and new protein synthesis. HDAC inhibition abrogated monocyte adhesion to inflamed endothelium suggesting that HDAC, specifically HDAC3, might be useful for the attenuation of the inflammatory response in ECs.

Key Words: cDNA microarray • HDAC • HUVEC • trichostatin A • VCAM-1

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