Hypoxia-inducible factor prolyl hydroxylase domain (PHD) inhibition after contusive spinal cord injury does not improve locomotor recovery.
Hypoxia-inducible factor prolyl hydroxylase domain (PHD) inhibition after contusive spinal cord injury does not improve locomotor recovery.
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DOI：
10.1371/journal.pone.0249591
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Hetman M
中科院分区：
文献类型：
--
作者：
Wei GZ;Saraswat Ohri S;Khattar NK;Listerman AW;Doyle CH;Andres KR;Karuppagounder SS;Ratan RR;Whittemore SR;Hetman M
创伤性脊髓损伤(SCI)是一种破坏性的神经系统疾病，包括原发和继发的组织丢失。各种细胞毒性事件，包括缺氧、出血和溶血、生物能量衰竭、氧化应激、内质网应激和神经炎症，都会导致继发性损伤。低氧诱导因子-1α(HIF-1α)家族是铁依赖的氧敏感酶，调节低氧诱导因子-1 DNA(HIF-1)的稳定性，并介导血液溶解释放的游离铁引起的氧化应激反应。抑制PHD通过减少激活转录因子4(ATF4)诱导的神经元死亡来改善实验性脑出血(ICH)后的预后。由于ATF4-CHOP(CCAAT-增强子结合蛋白同源蛋白)通路在挫伤性脊髓损伤的发病机制中起作用，我们在T9中度挫伤小鼠模型中观察了抑制PHD的作用，在该模型中，白质损伤是运动功能障碍的主要驱动因素。使用适配器喹(AQ)的药物抑制PHD可适度降低ATF4和CHOP mRNAs的急性诱导，并防止少突胶质细胞(OL)谱系mRNAs的急剧下降，但不能改善后肢运动的长期恢复或增加慢性白质储备。条件遗传消融OLS中的所有三种PHD同工酶不影响脊髓损伤后ATF4、CHOP或OL mRNAs的表达水平、运动恢复和白质保留。因此，对于涉及急性脑白质损伤的创伤性中枢神经系统病变，PHD可能不是改善预后的合适靶点。
Traumatic spinal cord injury (SCI) is a devastating neurological condition that involves both primary and secondary tissue loss. Various cytotoxic events including hypoxia, hemorrhage and blood lysis, bioenergetic failure, oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation contribute to secondary injury. The HIF prolyl hydroxylase domain (PHD/EGLN) family of proteins are iron-dependent, oxygen-sensing enzymes that regulate the stability of hypoxia inducible factor-1α (HIF-1α) and also mediate oxidative stress caused by free iron liberated from the lysis of blood. PHD inhibition improves outcome after experimental intracerebral hemorrhage (ICH) by reducing activating transcription factor 4 (ATF4)-driven neuronal death. As the ATF4-CHOP (CCAAT-enhancer-binding protein homologous protein) pathway plays a role in the pathogenesis of contusive SCI, we examined the effects of PHD inhibition in a mouse model of moderate T9 contusive SCI in which white matter damage is the primary driver of locomotor dysfunction. Pharmacological inhibition of PHDs using adaptaquin (AQ) moderately lowers acute induction of Atf4 and Chop mRNAs and prevents the acute decline of oligodendrocyte (OL) lineage mRNAs, but does not improve long-term recovery of hindlimb locomotion or increase chronic white matter sparing. Conditional genetic ablation of all three PHD isoenzymes in OLs did not affect Atf4, Chop or OL mRNAs expression levels, locomotor recovery, and white matter sparing after SCI. Hence, PHDs may not be suitable targets to improve outcomes in traumatic CNS pathologies that involve acute white matter injury.
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影响因子：
17.1
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
通讯作者：
Ratan RR
影响因子：
21.3
作者：
通讯作者：
--
影响因子：
25
作者：
Lin, Wensheng;Popko, Brian
通讯作者：
Popko, Brian
影响因子：
3.5
作者：
Fuss, B;Afshari, FS;Macklin, WB
通讯作者：
Macklin, WB
影响因子：
6.6
作者：
Niatsetskaya, Zoya;Basso, Manuela;Ratan, Rajiv R.
通讯作者：
Ratan, Rajiv R.