title: The Vitamin E Analog Gamma-Tocotrienol (GT3) and Statins Synergistically Up-Regulate Endothelial Thrombomodulin (TM).
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 increasedKLF2expression. 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.
authors.affiliation: Division of Radiation Health, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. rpathak@uams.edu.
authors.forename: Rupak
authors.initials: R
authors.lastname: Pathak
authors.affiliation: Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA. sanchita.ghosh@usuhs.edu.
authors.forename: Sanchita P
authors.initials: SP
authors.lastname: Ghosh
authors.affiliation: Division of Radiation Health, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. DZhou@uams.edu.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Division of Radiation Health, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. mhjensen@uams.edu.|Surgical Service, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA. mhjensen@uams.edu.
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D000069059:Atorvastatin / Q000494:pharmacology; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018180:Thrombomodulin / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002839:Chromans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D018180:Thrombomodulin; D014810:Vitamin E; C013649:plastochromanol 8; D000069059:Atorvastatin
keywords: Kruppel-like transcription factors; activated protein C; endothelial cells; gamma-tocotrienol; statins; thrombomodulin