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.
Highlights
A tightly packed monolayer of endothelial cells, called endothelium, lines all the blood vessels in the body
We found that a combined treatment of atorvastatin and GT3 synergistically up-regulate TM expression and its functional activity in primary human endothelial cells
To measure the effects of atorvastatin and GT3 on TM expression, primary human umbilical vein endothelial cells (HUVECs) were treated with different doses of atorvastatin and GT3 for 24 h and TM expression was measured by flow cytometry
Summary
A tightly packed monolayer of endothelial cells, called endothelium, lines all the blood vessels in the body. Statins have other therapeutic benefits, which include increasing the number of circulating endothelial progenitor cells, attenuating vascular smooth muscle cell proliferation, inhibiting platelet aggregation, stabilizing atherosclerotic plaques, suppressing vascular inflammation and adhesion, preventing dementia, and providing protection against radiation-induced normal tissue injury [20,21,22,23]. Despite these well-documented benefits, clinical studies indicate that statins may cause significant toxicity at high doses. We found that a combined treatment of atorvastatin and GT3 synergistically up-regulate TM expression and its functional activity in primary human endothelial cells
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