Dual effects of histone deacetylase inhibition by trichostatin A on endothelial nitric oxide synthase expression in endothelial cells

Biochem Biophys Res Commun. 2006 Feb 3;340(1):29-34. doi: 10.1016/j.bbrc.2005.11.151. Epub 2005 Dec 6.

Abstract

Inhibition of histone deacetylases by trichostatin A (TSA) has pleiotropic effects on gene expression. We demonstrated that at low dose (0.1 microg) TSA increased the eNOS mRNA levels, which was followed by a time- and dose-dependent down-regulation. Cycloheximide, a protein synthesis inhibitor, completely abolished TSA-induced decrease in eNOS expression, indicating that new protein synthesis is required for the inhibiting effect. Mevastatin--an inhibitor HMG-CoA reductase and geranylgeranylation reaction dose-dependently antagonized TSA-induced reduction. This mevastatin-mediated antagonism was completely abolished by geranylgeranylpyrophosphate, suggesting that geranylgeranyl modification is needed to activate the eNOS mRNA destabilizing factor--a mechanism responsible for statin-mediated eNOS upregulation.

Publication types

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

MeSH terms

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology*
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism*
  • Humans
  • Hydroxamic Acids / administration & dosage*
  • Nitric Oxide Synthase Type III / metabolism*

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • trichostatin A
  • Nitric Oxide Synthase Type III
  • Histone Deacetylases