On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death,ACS Central Science

当前位置： X-MOL 学术 › ACS Cent. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

On the Mechanism of Cytoprotection by Ferrostatin-1 and Liproxstatin-1 and the Role of Lipid Peroxidation in Ferroptotic Cell Death
ACS Central Science ( IF 12.7 ) Pub Date : 2017-03-07 00:00:00 , DOI: 10.1021/acscentsci.7b00028
Omkar Zilka ₁ , Ron Shah ₁ , Bo Li ₁ , José Pedro Friedmann Angeli ₂ , Markus Griesser ₁ , Marcus Conrad ₂ , Derek A. Pratt ₁

Affiliation

Ferroptosis is a form of regulated necrosis associated with the iron-dependent accumulation of lipid hydroperoxides that may play a key role in the pathogenesis of degenerative diseases in which lipid peroxidation has been implicated. High-throughput screening efforts have identified ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) as potent inhibitors of ferroptosis − an activity that has been ascribed to their ability to slow the accumulation of lipid hydroperoxides. Herein we demonstrate that this activity likely derives from their reactivity as radical-trapping antioxidants (RTAs) rather than their potency as inhibitors of lipoxygenases. Although inhibited autoxidations of styrene revealed that Fer-1 and Lip-1 react roughly 10-fold more slowly with peroxyl radicals than reactions of α-tocopherol (α-TOH), they were significantly more reactive than α-TOH in phosphatidylcholine lipid bilayers − consistent with the greater potency of Fer-1 and Lip-1 relative to α-TOH as inhibitors of ferroptosis. None of Fer-1, Lip-1, and α-TOH inhibited human 15-lipoxygenase-1 (15-LOX-1) overexpressed in HEK-293 cells when assayed at concentrations where they inhibited ferroptosis. These results stand in stark contrast to those obtained with a known 15-LOX-1 inhibitor (PD146176), which was able to inhibit the enzyme at concentrations where it was effective in inhibiting ferroptosis. Given the likelihood that Fer-1 and Lip-1 subvert ferroptosis by inhibiting lipid peroxidation as RTAs, we evaluated the antiferroptotic potential of 1,8-tetrahydronaphthyridinols (hereafter THNs): rationally designed radical-trapping antioxidants of unparalleled reactivity. We show for the first time that the inherent reactivity of the THNs translates to cell culture, where lipophilic THNs were similarly effective to Fer-1 and Lip-1 at subverting ferroptosis induced by either pharmacological or genetic inhibition of the hydroperoxide-detoxifying enzyme Gpx4 in mouse fibroblasts, and glutamate-induced death of mouse hippocampal cells. These results demonstrate that potent RTAs subvert ferroptosis and suggest that lipid peroxidation (autoxidation) may play a central role in the process.

中文翻译：

关于Ferrostatin-1和Liproxstatin-1的细胞保护机制以及脂质过氧化作用在肥大细胞死亡中的作用

Ferroptosis是一种与坏死的形式有关的脂质坏死，与脂质氢过氧化物的铁依赖性积累有关，可能在涉及脂质过氧化的变性疾病的发病机理中起关键作用。高通量的筛选工作已确定，ferrostatin-1（Fer-1）和liproxstatin-1（Lip-1）可作为肥大症的有效抑制剂-这种活性归因于其减缓脂质过氧化氢积累的能力。在本文中，我们证明了这种活性可能源自其作为自由基捕获抗氧化剂（RTA）的反应性，而不是其作为脂氧合酶抑制剂的效力。尽管抑制了苯乙烯的自氧化，发现Fer-1和Lip-1与过氧自由基的反应比α-生育酚（α-TOH）的反应慢大约10倍，它们在磷脂酰胆碱脂质双层中的反应性明显强于α-TOH，这与Fer-1和Lip-1相对于α-TOH作为促肥大症抑制剂相比具有更高的效力相一致。当以抑制Fertroposis的浓度进行测定时，Fer-1，Lip-1和α-TOH均未抑制在HEK-293细胞中过表达的人15-脂氧合酶-1（15-LOX-1）。这些结果与用已知的15-LOX-1抑制剂（PD146176）获得的结果形成鲜明对比，后者可以在有效抑制铁锈病的浓度下抑制该酶。鉴于Fer-1和Lip-1通过抑制脂质过氧化而将肥大症转化为RTAs的可能性，我们评估了1,8-四氢萘啶醇（以下称为THNs）的抗铁肥潜力：合理设计的具有无与伦比的反应性的自由基捕获抗氧化剂。我们首次显示THNs的内在反应性转化为细胞培养物，其中亲脂性THNs在颠覆由氢过氧化物解毒酶Gpx4的药理或遗传抑制所致的促肥大作用方面与Fer-1和Lip-1类似地有效。小鼠成纤维细胞和谷氨酸诱导的小鼠海马细胞死亡。这些结果表明有效的RTA可以颠覆肥大症，并表明脂质过氧化作用（自氧化作用）可能在该过程中发挥重要作用。和谷氨酸诱导的小鼠海马细胞死亡。这些结果表明有效的RTA可以颠覆肥大症，并表明脂质过氧化作用（自氧化作用）可能在该过程中发挥重要作用。和谷氨酸诱导的小鼠海马细胞死亡。这些结果表明有效的RTA可以颠覆肥大症，并表明脂质过氧化作用（自氧化作用）可能在该过程中发挥重要作用。

更新日期：2017-03-07

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南