gamma-Tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative stress after total-body irradiation by an HMG-CoA reductase-dependent mechanism.
gamma-Tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative stress after total-body irradiation by an HMG-CoA reductase-dependent mechanism.
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DOI：
10.1667/rr1632.1
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发表时间：
2009-05
影响因子：
3.4
通讯作者：
Hauer-Jensen M
中科院分区：
文献类型：
--
作者：
Berbée M;Fu Q;Boerma M;Wang J;Kumar KS;Hauer-Jensen M
维生素E的类似物（工具）由于其高效性和低毒性，正在开发作为放射性预防剂。γ -生育三烯醇（GT3）是特别有趣的，因为它除了是一种抗氧化剂外，还能抑制3-羟基-3-甲基戊二酰辅酶A （HMG-CoA）还原酶，并且在内皮细胞中积累的程度比其他工具更大。我们在体内研究了HMG-CoA还原酶抑制是否有助于GT3赋予的辐射防护。各组小鼠分别给药、甲羟戊酸（由HMG-CoA还原酶催化的反应产物）、GT3单独或GT3与甲羟戊酸联合。对全身照射后的造血、肠道和血管/内皮系统的致死率和损伤标准参数进行评估。GT3改善了辐照后的生存，降低了辐射诱导的血管氧化应激，甲羟戊酸可逆转这一作用。GT3还能促进造血恢复，减轻肠道辐射损伤，加速内皮功能可溶性标志物的恢复。这些参数在甲羟戊酸联合给药时没有逆转。我们的数据证实了GT3对造血损伤的放射性预防特性，并首次证明了GT3在保护胃肠道和血管损伤方面的益处。GT3对血管损伤的辐射防护作用与其作为HMG-CoA还原酶抑制剂的特性有关。
Analogs of vitamin E (tocols) are under development as radioprophylactic agents because of their high efficacy and lack of toxicity. Gamma-tocotrienol (GT3) is of particular interest because, in addition to being an antioxidant, it also inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and accumulates to greater extent in endothelial cells than other tocols. We addressed in vivo whether HMG-CoA reductase inhibition contributes to the radioprotection conferred by GT3. Groups of mice were treated with vehicle, mevalonate (the product of the reaction catalyzed by HMG-CoA reductase), GT3 alone or GT3 in combination with mevalonate. Lethality and standard parameters of injury to the hematopoietic, intestinal and vascular/endothelial systems were assessed after exposure to total-body irradiation. GT3 improved post-irradiation survival and decreased radiation-induced vascular oxidative stress, an effect that was reversible by mevalonate. GT3 also enhanced hematopoietic recovery, reduced intestinal radiation injury, and accelerated the recovery of soluble markers of endothelial function. These parameters were not reversed by mevalonate co-administration. Our data confirm GT3’s radioprophylactic properties against hematopoietic injury and, for the first time, demonstrate benefits in terms of protection against gastrointestinal and vascular injury. The radioprotective efficacy of GT3 against vascular injury is related to its properties as an HMG-CoA reductase inhibitor.