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Int J Mol Sci. 2016 Nov 18;17(11). pii: E1937.

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

Author information

1
Division of Radiation Health, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. rpathak@uams.edu.
2
Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA. sanchita.ghosh@usuhs.edu.
3
Division of Radiation Health, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. DZhou@uams.edu.
4
Division of Radiation Health, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. mhjensen@uams.edu.
5
Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA. mhjensen@uams.edu.

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.

KEYWORDS:

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

PMID:
27869747
PMCID:
PMC5133932
DOI:
10.3390/ijms17111937
[Indexed for MEDLINE]
Free PMC Article

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