Histone deacetylase inhibitor reduces monocyte adhesion to endothelium through the suppression of vascular cell adhesion molecule-1 expression

Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2652-9. doi: 10.1161/01.ATV.0000247247.89787.e7. Epub 2006 Sep 28.

Abstract

Objective: Tumor necrosis factor (TNF)-alpha initiates numerous changes in endothelial cell (EC) gene expression that contributes to the pathology of various diseases including inflammation. We hypothesized that TNF-alpha-mediated gene induction involves multiple signaling pathways, and that inhibition of one or more of these pathways may selectively target subsets of TNF-alpha-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-alpha at 4 hours and analyzed by microarray. TNF-alpha-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-alpha-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-alpha-mediated VCAM-1 expression.

Conclusions: TNF-alpha 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Chromones / pharmacology
  • E-Selectin / genetics
  • E-Selectin / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Histone Deacetylases / physiology
  • Humans
  • Hydroxamic Acids / pharmacology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Leupeptins / pharmacology
  • Mice
  • Mice, Transgenic
  • Monocytes / cytology*
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Morpholines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism*

Substances

  • Azepines
  • Chromones
  • E-Selectin
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • K 11430
  • Leupeptins
  • Morpholines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • trichostatin A
  • Histone Deacetylases
  • histone deacetylase 3
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde