on September 28, 2006
Published online before print September 28, 2006, doi: 10.1161/01.ATV.0000247247.89787.e7
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Submitted on March 10, 2006
Accepted on August 27, 2006
Histone Deacetylase Inhibitor Reduces Monocyte Adhesion to Endothelium Through the Suppression of Vascular Cell Adhesion Molecule-1 Expression
Kenji Inoue ;
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.
* To whom correspondence should be addressed. 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.
Key words: cDNA microarray • HDAC • HUVEC • trichostatin A • VCAM-1
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