This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/12/2652    most recent 01.ATV.0000247247.89787.e7v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inoue, K. Articles by Minami, T. Search for Related Content PubMed PubMed Citation Articles by Inoue, K. Articles by Minami, T.

(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

This article has been cited by other articles:

				Y. Wada, Y. Ohta, M. Xu, S. Tsutsumi, T. Minami, K. Inoue, D. Komura, J. Kitakami, N. Oshida, A. Papantonis, et al. A wave of nascent transcription on activated human genes PNAS, October 27, 2009; 106(43): 18357 - 18361. [Abstract] [Full Text] [PDF]

				D. G. Binion, J. Heidemann, M. S. Li, V. M. Nelson, M. F. Otterson, and P. Rafiee Vascular cell adhesion molecule-1 expression in human intestinal microvascular endothelial cells is regulated by PI 3-kinase/Akt/MAPK/NF-{kappa}B: inhibitory role of curcumin Am J Physiol Gastrointest Liver Physiol, August 1, 2009; 297(2): G259 - G268. [Abstract] [Full Text] [PDF]

				C.-W. Lee, C.-C. Lin, S.-F. Luo, H.-C. Lee, I.-T. Lee, W. C. Aird, T.-L. Hwang, and C.-M. Yang Tumor Necrosis Factor-{alpha} Enhances Neutrophil Adhesiveness: Induction of Vascular Cell Adhesion Molecule-1 via Activation of Akt and CaM Kinase II and Modifications of Histone Acetyltransferase and Histone Deacetylase 4 in Human Tracheal Smooth Muscle Cells Mol. Pharmacol., May 1, 2008; 73(5): 1454 - 1464. [Abstract] [Full Text] [PDF]

				C. C. Matouk and P. A. Marsden Epigenetic Regulation of Vascular Endothelial Gene Expression Circ. Res., April 25, 2008; 102(8): 873 - 887. [Abstract] [Full Text] [PDF]

				J. Wang, S. A. Mahmud, P. B. Bitterman, Y. Huo, and A. Slungaard Histone Deacetylase Inhibitors Suppress TF-{kappa}B-dependent Agonist-driven Tissue Factor Expression in Endothelial Cells and Monocytes J. Biol. Chem., September 28, 2007; 282(39): 28408 - 28418. [Abstract] [Full Text] [PDF]

				H.-J. Sung, A. Yee, S. G. Eskin, and L. V. McIntire Cyclic strain and motion control produce opposite oxidative responses in two human endothelial cell types Am J Physiol Cell Physiol, July 1, 2007; 293(1): C87 - C94. [Abstract] [Full Text] [PDF]