Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress
Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress
复制标题
DOI：
10.1128/mcb.24.16.7214-7224.2004
复制
发表时间：
2004-08-01
影响因子：
5.3
通讯作者：
Galland, F
中科院分区：
文献类型：
--
作者：
Berruyer, C;Martin, FM;Galland, F
Vanin-1是一种具有泛酸酶活性的上皮外酶，通过泛酸（维生素B-5）的代谢产生氨基巯基半胱胺。本研究表明，组织中缺乏半胱胺的Vanin-1（-/-）小鼠对全身γ辐照或百草枯诱导的氧化损伤表现出抵抗性。这种保护作用与减少细胞凋亡和炎症有关，并通过用半胺治疗突变动物而逆转。Vanin-1（-/-）小鼠更好的耐受性与肝脏中γ -谷氨酰胺合成酶活性的增强有关，可能是由于缺乏半胱胺，导致谷胱甘肽（GSH）的储存增加，谷胱甘肽是最有效的细胞抗氧化剂。因此，在暴露于辐照后，Vanin-1（-/-）小鼠在组织中保持了一个更低的环境。在正常小鼠中，我们发现应激诱导的Vanin-1双相表达通过其启动子区域的抗氧化反应元件调节。这个过程应该能很好地调节氧化还原环境，从而将早期的炎症过程转变为晚期的组织修复过程。我们提出Vanin-1是在上皮水平上调节gsh依赖性氧化损伤反应的关键分子。因此，Vanin/pantetheinase抑制剂可用于治疗因辐照和促氧化诱导剂引起的损伤。
Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B-5). Here we show that Vanin-1(-/-) mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body gamma-irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1(-/-) mice is associated with an enhanced gamma-glutamyleysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1(-/-) mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.