Pathak Rupak, Ghosh Sanchita P, Zhou Daohong, Hauer-Jensen Martin
Division of Radiation Health, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA.
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 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.
他汀类药物是一类常规处方的降胆固醇药物，可抑制3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR），并强烈诱导内皮血栓调节蛋白（TM），已知TM具有抗炎、抗凝、抗氧化和辐射防护特性。然而，高剂量毒性限制了他汀类药物的临床应用。维生素E家族成员γ-生育三烯酚（GT3）也能抑制HMGCR活性并诱导TM表达，即使在高浓度下也不会引起明显的不良副作用。为了研究他汀类药物和GT3对TM的协同作用，使用低剂量的阿托伐他汀和GT3处理人原代内皮细胞。通过流式细胞术测量蛋白质水平的TM表达。通过活化蛋白C（APC）生成试验确定TM的功能活性。通过定量逆转录聚合酶链反应（qRT-PCR）测量TM的关键转录因子之一Kruppel样因子2（KLF2）的表达。阿托伐他汀和GT3处理后，TM表达均呈剂量依赖性增加。低剂量阿托伐他汀和GT3联合处理可协同上调TM表达和功能活性。最后，阿托伐他汀和GT3协同增加了表达。这些发现表明，他汀类药物与GT3联合治疗可能在治疗多种病理生理状况（包括炎症和心血管疾病）方面带来显著的健康益处。
