Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.
Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models.
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DOI：
10.1126/scitranslmed.aac6008
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发表时间：
2016-03-02
影响因子：
17.1
通讯作者：
Ratan RR
中科院分区：
文献类型：
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作者：
Karuppagounder SS;Alim I;Khim SJ;Bourassa MW;Sleiman SF;John R;Thinnes CC;Yeh TL;Demetriades M;Neitemeier S;Cruz D;Gazaryan I;Killilea DW;Morgenstern L;Xi G;Keep RF;Schallert T;Tappero RV;Zhong J;Cho S;Maxfield FR;Holman TR;Culmsee C;Fong GH;Su Y;Ming GL;Song H;Cave JW;Schofield CJ;Colbourne F;Coppola G;Ratan RR
脑出血（ICH）导致的残疾或死亡归因于血液溶解、铁释放和随之而来的氧化应激。铁螯合剂与游离铁结合并防止氧化应激诱导的神经元死亡和ICH所致的残疾，但这种作用的机制仍不清楚。我们表明，缺氧诱导因子脯氨酰羟化酶结构域（HIF-PHD）家族的铁依赖性，氧敏感酶的铁螯合效应。在小鼠纹状体中三种HIF-PHD酶亚型的分子减少改善了ICH后的功能恢复。在几种啮齿动物模型中，HIF-PHD酶的低分子量羟基喹啉抑制剂adaptaquin减少了ICH后的神经元死亡和行为缺陷，而不影响脑中的总铁或锌分布。出乎意料的是，adaptaquin对体外氧化死亡或体内ICH的保护作用与抑制促死亡因子ATF 4的活性有关，而不是激活HIF依赖性促存活途径。总之，这些发现表明，在几种啮齿动物模型中，用血脑屏障渗透性抑制剂adaptaquin对HIF-PHD金属酶进行脑特异性灭活可以改善ICH后的功能结局。
Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models.