Rasd1促进少突胶质细胞铁死亡加重大鼠蛛网膜下腔出血后白质损伤

傅汶桥; 车旭东; 谭嘉禾; 崔仕振; 马寅瑞; 徐代棋; 龙海波; 杨小林; 文唐敏; 何朝晖

doi:10.16016/j.2097-0927.202302069

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Rasd1促进少突胶质细胞铁死亡加重大鼠蛛网膜下腔出血后白质损伤

基础医学 | 更新时间：2026-01-09

- Rasd1促进少突胶质细胞铁死亡加重大鼠蛛网膜下腔出血后白质损伤
- Rasd1 aggravates white matter injury after subarachnoid hemorrhage in rats by promoting ferroptosis in oligodendrocytes
- 陆军军医大学学报 2023年45卷第17期页码：1819-1827
- 作者机构：
  
  400016 重庆，重庆医科大学附属第一医院神经外科
- 作者简介：
  
  [何朝晖，E-mail: hezhaohui@hospital.cqmu.edu.cnHE Zhaohui, E-mail: hezhaohui@hospital.cqmu.edu.cn
- 基金信息：
  
  ‍基‍金‍项‍目‍］‍ ‍国家自然科学基金面上项目(81870927)
- DOI：10.16016/j.2097-0927.202302069
  中图分类号： R341;R363.21;R743.35
- 收稿：2023-02-13，
  
  修回：2023-03-17，
  
  纸质出版：2023-09-15
- 稿件说明：
移动端阅览
傅汶桥, 车旭东, 谭嘉禾, 等. Rasd1促进少突胶质细胞铁死亡加重大鼠蛛网膜下腔出血后白质损伤[J]. 陆军军医大学学报, 2023,45(17):1819-1827.

Wenqiao FU, Xudong CHE, Jiahe TAN, et al. Rasd1 aggravates white matter injury after subarachnoid hemorrhage in rats by promoting ferroptosis in oligodendrocytes[J]. Journal of Army Medical University, 2023, 45(17): 1819-1827.
傅汶桥, 车旭东, 谭嘉禾, 等. Rasd1促进少突胶质细胞铁死亡加重大鼠蛛网膜下腔出血后白质损伤[J]. 陆军军医大学学报, 2023,45(17):1819-1827. DOI： 10.16016/j.2097-0927.202302069.

Wenqiao FU, Xudong CHE, Jiahe TAN, et al. Rasd1 aggravates white matter injury after subarachnoid hemorrhage in rats by promoting ferroptosis in oligodendrocytes[J]. Journal of Army Medical University, 2023, 45(17): 1819-1827. DOI： 10.16016/j.2097-0927.202302069.

摘要

目的

探索Rasd1(ras related dexamethasone induced 1)在SD大鼠蛛网膜下腔出血(subarachnoid hemorrhage

SAH)后通过神经元-少突胶质细胞间通讯参与白质损伤(white matter injury

WMI)的机制。

方法

将90只雄性SD大鼠(体质量180~250 g)采用随机抽签的方法分为假手术组、SAH组、SAH+LV-NC组、SAH+LV-Rasd1组和SAH+sh-Rasd1组

最终每组12只。利用血管内穿刺法构建大鼠在体SAH模型

侧脑室注射Rasd1基因过表达/敲低慢病毒

神经行为学评分检测神经功能变化

透射电镜检测胼胝体区域髓鞘脱失情况和少突胶质细胞铁死亡的发生情况

普鲁士蓝染色检测铁沉积

试剂盒检测丙二醛(malonic dialdehyde

MDA)和谷胱甘肽(glutathione

GSH)

PCR检测Rasd1 mRNA的表达情况

Western blot检测核受体辅激活蛋白4(nuclear receptor coactivator 4

NCOA4)、谷胱甘肽过氧化物酶4(glutathione peroxidase 4

GPX4)、2'

3'-环腺苷酸-3'-磷酸二酯酶(2'

3'-cyclic-nucleotide 3'-phosphodiesterase

CNPase)和铁蛋白(Ferritin)的表达。

结果

SAH后

Rasd1升高(

0.01)并主要表达于皮层神经元中

出现髓鞘脱失

少突胶质细胞铁死亡; 过表达Rasd1后

大鼠神经行为学评分显著降低

髓鞘脱失、少突胶质细胞铁死亡和铁沉积明显加重

MDA升高(

0.01)、GSH下降(

0.01)、NCOA4升高(

0.01)、Ferritin和GPX4下降(

0.01);敲低Rasd1后

大鼠神经行为学评分明显升高

髓鞘脱失、少突胶质细胞铁死亡和铁沉积显著减轻

MDA下降(

0.01)、GSH升高(

0.01)、NCOA4下降(

0.01)、Ferritin和GPX4升高(

0.01)。

结论

Rasd1在蛛网膜下腔出血后通过铁自噬促进少突胶质细胞铁死亡

从而参与蛛网膜下腔出血后白质损伤。

Abstract

Objective

To explore the underlying mechanism in which Ras related dexamethasone induced 1(Rasd1) is involved in white matter injury through neuron-oligodendrocyte communication after subarachnoid hemorrhage (SAH) in SD rats.

Methods

Ninety male SD rats (180~250 g) were randomly divided into sham operation group

SAH group

SAH+LV-NC group

SAH+LV-Rasd1 group and SAH+sh-Rasd1 group

with 12 rats in each group.Intravascular puncture was used to construct the rat model of SAH.Rasd1 overexpression/knockdown lentivirus was injected into the lateral ventricle.Neurobehavioral rating scale was used to observe the changes in neural function

transmission electron microscopy was employed to detect the myelin detachment in callosum region and the occurrence of ferroptosis in oligodendrocytes

and Prussian blue staining was applied to measure iron deposition.Malondialdehyde (MDA) and glutathione (GSH) contents were detected with corresponding reagent kits

Rasd1 mRNA level was detected by PCR

and protein levels of nuclear receptor coactivator 4(NCOA4)

2′

3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase)

glutathione peroxidase 4(GPX4) and ferritin were measured with Western blotting.

Results

SAH resulted in significantly highly expressed Rasd1

which was mainly distributed in the cortical neurons (

0.01)

myelin loss

and ferroptosis in oligodendrocytes.Rasd1 overexpression significantly reduced the neurobehavioral scores

but increased myelin loss

ferroptosis and iron deposition in oligodendrocytes

elevated MDA content (

0.01) but decreased GSH content (

0.01)

and up-regulation of NCOA4 expression (

0.01) and down-regulation of ferritin and GPX4(

0.01).However

Rasd1 knockdown reversed all above change

s with statistical significances (all

0.01).

Conclusion

Rasd1 promotes ferroptosis in oligodendrocytes through ferritinophagy

and then is involved in white matter injury after SAH.

关键词

Keywords

references

LAWTON M T, VATES G E. Subarachnoid hemorrhage[J]. N Engl J Med, 2017, 377(3): 257-266. DOI: 10.1056/NEJMcp1605827.

JIANG Y B, WEI K Y, ZHANG X Y, et al . White matter repair and treatment strategy after intracerebral hemorrhage[J ] . CNS Neurosci Ther, 2019, 25(10): 1113-1125. DOI: 10.1111/cns.13226.

TANG D L, KROEMER G. Ferroptosis[J]. Curr Biol, 2020, 30(21): R1292-R1297. DOI: 10.1016/j.cub.2020.09.068.

LI J, CAO F, YIN H L, et al . Ferroptosis: past, present and future[J ] . Cell Death Dis, 2020, 11(2): 88. DOI: 10.1038/s41419-020- 2298-2.

FANG M, JAFFREY S R, SAWA A, et al . Dexras1: a G protein specifically coupled to neuronal nitric oxide synthase via CAPON[J ] . Neuron, 2000, 28(1): 183-193. DOI: 10.1016/s0896-6273(00)00095-7..

CHENG H Y, OBRIETAN K, CAIN S W, et al . Dexras1 potentiates photic and suppresses nonphotic responses of the circadian clock[J ] . Neuron, 2004, 43(5): 715-728. DOI: 10.1016/j.neuron.2004.08.021.

GREENWOOD M P, GREENWOOD M, MECAWI A S, et al . Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation[J ] . Mol Brain, 2016, 9: 1. DOI: 10.1186/s13041-015-0182-2.

WANG Y, DONG X H, LI Z Z, et al . Downregulated RASD1 and upregulated miR-375 are involved in protective effects of calycosin on cerebral ischemia/reperfusion rats[J ] . J Neurol Sci, 2014, 339(1/2): 144-148. DOI: 10.1016/j.jns.2014.02.002.

QIAN Z M, KE Y. Brain iron transport[J]. Biol Rev Camb Philos Soc, 2019, 94(5): 1672-1684. DOI: 10.1111/brv.12521.

MO J, ENKHJARGAL B, TRAVIS Z D, et al . AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats[J ] . Redox Biol, 2019, 20: 75-86. DOI: 10.1016/j.redox.2018.09.022..

XU P F, TAO C R, ZHU Y Y, et al . TAK1 mediates neuronal pyroptosis in early brain injury after subarachnoid hemorrhage[J ] . J Neuroinflam, 2021, 18(1): 188. DOI: 10.1186/s12974-021-02226-8.

XIA D Y, YUAN J L, JIANG X C, et al . SIRT1 promotes M2 microglia polarization via reducing ROS-mediated NLRP3 inflammasome signaling after subarachnoid hemorrhage[J ] . Front Immunol, 2021, 12: 770744. DOI: 10.3389/fimmu.2021.770744.

PENG J H, PANG J W, HUANG L, et al . LRP1 activation attenuates white matter injury by modulating microglial polarization through Shc1/PI3K/Akt pathway after subarachnoid hemorrhage in rats[J ] . Redox Biol, 2019, 21: 101121. DOI: 10.1016/j.redox.2019.101121.

LIANG Y D, DENG Y B, ZHAO J, et al . Ferritinophagy is involved in experimental subarachnoid hemorrhage-induced neuronal ferroptosis[J ] . Neurochem Res, 2022, 47(3): 692-700. DOI: 10.1007/s11064-021-03477-w.

TAO T, LIU G J, SHI X, et al . DHEA attenuates microglial activation via induction of JMJD3 in experimental subarachnoid haemorrhage[J ] . J Neuroinflam, 2019, 16(1): 243. DOI: 10.1186/s12974-019-1641-y..

CAO Y, LI Y, HE C, et al . Selective ferroptosis inhibitor liproxstatin-1 attenuates neurological deficits and neuroinflammation after subarachnoid hemorrhage[J ] . Neurosci Bull, 2021, 37(4): 535-549. DOI: 10.1007/s12264-020-00620-5.

罗鹏, 费舟. 颅脑损伤相关创伤后应激障碍的研究进展[J]. 空军军医大学学报, 2022(4): 487-490, 494.

PENG L, ZHOU F. Research advances in posttraumatic stress disorder following traumatic brain injury[J]. J Air Force Med Univ, 2022(4): 487-490, 494.

CHAVALI M, ULLOA-NAVAS M J, PÉREZ-BORREDÁ P, et al . Wnt-dependent oligodendroglial-endothelial interactions regulate white matter vascularization and attenuate injury[J ] . Neuron, 2020, 108(6): 1130-1145. e5. DOI: 10.1016/j.neuron.2020.09.033.

MOUJALLED D, STRASSER A, LIDDELL J R. Molecular mechanisms of cell death in neurological diseases[J]. Cell Death Differ, 2021, 28(7): 2029-2044. DOI: 10.1038/s41418-021-00814-y.

FENG Z, MIN L X, CHEN H, et al . Iron overload in the motor cortex induces neuronal ferroptosis following spinal cord injury[J ] . Redox Biol, 2021, 43: 101984. DOI: 10.1016/j.redox.2021.101984.

ZHANG H X, OSTROWSKI R, JIANG D Z, et al . Hepcidin promoted ferroptosis through iron metabolism which is associated with DMT1 signaling activation in early brain injury following subarachnoid hemorrhage[J ] . Oxid Med Cell Longev, 2021, 2021: 9800794. DOI: 10.1155/2021/9800794.

ZHANG Y, ZHU Z, LIANG H Y, et al . nNOS-CAPON interaction mediates amyloid-β-induced neurotoxicity, especially in the early stages[J ] . Aging Cell, 2018, 17(3): e12754. DOI: 10.1111/acel.12754.

SEOK J W, KIM D, YOON B K, et al . Dexras1 plays a pivotal role in maintaining the equilibrium between adipogenesis and osteogenesis[J ] . Metabolism, 2020, 108: 154250. DOI: 10.1016/j.metabol.2020.154250.

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