The vitamin E analog gamma-tocotrienol (GT3) and statins synergistically up-regulate endothelial thrombomodulin (TM)

Rupak Pathak, Sanchita P. Ghosh, Daohong Zhou, Martin Hauer-Jensen

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number1937
JournalInternational journal of molecular sciences
Volume17
Issue number11
DOIs
StatePublished - Nov 18 2016
Externally publishedYes

Keywords

  • Activated protein C
  • Endothelial cells
  • Gamma-tocotrienol
  • Kruppel-like transcription factors
  • Statins
  • Thrombomodulin

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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