The Vitamin E Analog Gamma-Tocotrienol (GT3) and Statins Synergistically Up-Regulate Endothelial Thrombomodulin (TM)

Int J Mol Sci. 2016 Nov 18;17(11):1937. doi: 10.3390/ijms17111937.


Statins; a class of routinely prescribed cholesterol-lowering drugs; inhibit 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) and strongly induce endothelial thrombomodulin (TM); which is known to have anti-inflammatory; anti-coagulation; anti-oxidant; and radioprotective properties. However; high-dose toxicity limits the clinical use of statins. The vitamin E family member gamma-tocotrienol (GT3) also suppresses HMGCR activity and induces TM expression without causing significant adverse side effects; even at high concentrations. To investigate the synergistic effect of statins and GT3 on TM; a low dose of atorvastatin and GT3 was used to treat human primary endothelial cells. Protein-level TM expression was measured by flow cytometry. TM functional activity was determined by activated protein C (APC) generation assay. Expression of Kruppel-like factor 2 (KLF2), one of the key transcription factors of TM, was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). TM expression increased in a dose-dependent manner after both atorvastatin and GT3 treatment. A combined treatment of a low-dose of atorvastatin and GT3 synergistically up-regulated TM expression and functional activity. Finally; atorvastatin and GT3 synergistically increased KLF2 expression. These findings suggest that combined treatment of statins with GT3 may provide significant health benefits in treating a number of pathophysiological conditions; including inflammatory and cardiovascular diseases.

Keywords: Kruppel-like transcription factors; activated protein C; endothelial cells; gamma-tocotrienol; statins; thrombomodulin.

MeSH terms

  • Antioxidants / pharmacology
  • Atorvastatin / pharmacology
  • Cell Line
  • Chromans / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Flow Cytometry
  • Gene Expression Regulation / drug effects
  • Human Umbilical Vein Endothelial Cells / drug effects*
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thrombomodulin / genetics*
  • Thrombomodulin / metabolism
  • Up-Regulation / drug effects
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology


  • Antioxidants
  • Chromans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • KLF2 protein, human
  • Kruppel-Like Transcription Factors
  • Thrombomodulin
  • Vitamin E
  • plastochromanol 8
  • Atorvastatin