Fibroblasts derived from Gpx1 knockout mice display senescent-like features and are susceptible to H2O2-mediated cell death
Fibroblasts derived from Gpx1 knockout mice display senescent-like features and are susceptible to H2O2-mediated cell death
复制标题
DOI：
10.1016/j.freeradbiomed.2003.10.020
复制
发表时间：
2004-01-01
影响因子：
7.4
通讯作者：
Kola, I
中科院分区：
文献类型：
--
作者：
de Haan, JB;Bladier, C;Kola, I
衰老的自由基理论认为，活性氧自由基(ROS)参与了衰老的病理生理过程。我们以前的数据强调了抗氧化酶，超氧化物歧化酶1(SOD1)和谷胱甘肽过氧化物酶1(GPX1)在调节这一过程中的重要性。此前，我们证明了SOD1与GPX1比率的扰动，作为SOD I过度表达的结果，导致了衰老样的变化。我们认为这是通过SOD1歧化产物过氧化氢介导的，因为过氧化氢在对照细胞中引起了类似的变化。然而，有人认为，通过SOD1歧化产生过氧化氢的速率受到底物O-2(.-)的可用性的限制，因此SOD1的其他功能可能会发生与年龄相关的变化。在这项研究中，我们在来自GPX1缺失突变小鼠(GPX1-/-)的成纤维细胞中测试了这一概念，这些突变小鼠由于GPX1没有清除过氧化氢而导致过氧化氢升高。我们展示了GPX1-/-成纤维细胞的衰老样变化，包括(1)增殖能力、DNA合成以及对EGF和血清的反应性降低；(2)Cipl水平升高；(3)NF-kappaB活性增强；(4)衰老细胞的形态特征。GPX1-/-成纤维细胞对过氧化氢诱导的细胞凋亡也表现出剂量依赖的敏感性。我们的发现表明，GPX1对ROS介导的类衰老变化和氧化剂介导的细胞死亡都具有保护作用。(C)2003 Elsevier Inc.保留所有权利。
The Free Radical Theory of Aging proposes that reactive oxygen species (ROS) contribute to the pathophysiology of aging. Our previous data highlight the importance of antioxidant enzymes, superoxide dismutase 1 (Sod1) and glutathione peroxidase 1 (Gpx1), in regulating this process. Previously, we demonstrated that a perturbation in the Sod1-to-Gpx1 ratio, as a consequence of Sod I overexpression, leads to senescence-like changes. We proposed that this was mediated via the Sod1 dismutation product H2O2, because H2O2 induced similar changes in control cells. However, it has been suggested that H2O2 production, via Sod1 dismutation, is rate-limited by the availability of the substrate O-2(.-), and therefore age-related changes may occur as a result of other functions of Sod1. In this study, we test this notion in fibroblasts derived from Gpx1 null mutant mice (Gpx1-/-) that have elevated H2O2 as a consequence of the lack of its removal by Gpx1. We demonstrate senescence-like changes in Gpx1-/- fibroblasts that include (1) reduced proliferative capacity, DNA synthesis, and responsiveness to EGF and serum; (2) elevated levels of Cipl; (3) increased NF-kappaB activation; and (4) morphological features of senescent cells. Gpx1-/- fibroblasts also demonstrate a dose-dependent susceptibility to H2O2-induced apoptosis. Our findings suggest that Gpx1 is protective against both ROS-mediated senescence-like changes and oxidant-mediated cell death. (C) 2003 Elsevier Inc. All rights reserved.