收稿日期: 2025-04-25
网络出版日期: 2025-12-18
基金资助
国家健康卫生委高血压诊疗研究重点实验室开放课题(NHC Key Laboratory of Hypertension Clinical Research 2024-05)
Chronic intermittent hypoxia induces hippocampal neuronal apoptosis by activating endoplasmic reticulum stress via calcium overload
Received date: 2025-04-25
Online published: 2025-12-18
目的 探讨慢性间歇性低氧（CIH）对大鼠海马神经元的损伤作用及其与内质网（ER）应激相关凋亡通路的关系。 方法 将雄性SD大鼠随机分为对照组和CIH组，每组各8只。CIH组大鼠每天暴露于间歇性低氧环境8 h，持续8周。采用HE染色与透射电镜观察海马组织神经元形态学变化；TUNEL法检测神经元凋亡；流式细胞术测定胞内Ca2?水平；qPCR与Western blot检测GRP78、CHOP和Caspase-3的mRNA及蛋白表达。 结果 与对照组相比，CIH组大鼠海马神经元出现明显形态学损伤，包括细胞排列紊乱、胞浆溶解及粗面内质网肿胀；TUNEL检测显示凋亡细胞数显著增加（P < 0.05）；流式检测提示胞内Ca2?水平升高（P < 0.05）；GRP78、CHOP和Caspase-3的mRNA及蛋白水平均明显上调（P < 0.05）。 结论 CIH可导致大鼠海马神经元显著损伤和凋亡，其机制与Ca2?稳态紊乱介导的ER应激及下游凋亡通路激活密切相关。
李瑜 , 陈玉岚 , 连思念 , 王红 . 慢性间歇性低氧通过钙超载激活内质网应激诱导海马神经元凋亡[J]. 实用医学杂志, 2025 , 41(23) : 3659 -3665 . DOI: 10.3969/j.issn.1006-5725.2025.23.005
Objective To investigate the effects of chronic intermittent hypoxia （CIH） on hippocampal neuronal injury in rats， and to clarify the role of endoplasmic reticulum （ER） stress?related apoptotic pathways. Methods Male Sprague?Dawley rats were randomly assigned to a control group （n = 8） or a CIH group （n = 8）. The CIH group was exposed to intermittent hypoxia for 8 h/day over 8 weeks. Hippocampal neuronal morphology was examined by hematoxylin?eosin staining and transmission electron microscopy. Neuronal apoptosis was assessed using the TUNEL assay. Intracellular Ca2? levels were measured by flow cytometry. The mRNA and protein expression of ER stress?related factors （GRP78， CHOP） and the apoptotic effector Caspase-3 were quantified by qPCR and Western blot. Results Compared with controls， rats in the CIH group exhibited marked hippocampal neuronal damage， including disrupted cytoarchitecture， cytoplasmic dissolution， and swollen rough ER. Ultrastructural analysis revealed nuclear deformation and organelle disruption. TUNEL assay demonstrated a significant increase in apoptotic cells （P < 0.05）. Flow cytometry showed elevated intracellular Ca2? levels （P < 0.05）. GRP78， CHOP， and Caspase-3 were significantly upregulated at both mRNA and protein levels in the CIH group （all P < 0.05）. Conclusion CIH induces pronounced hippocampal neuronal injury and apoptosis in rats， associated with Ca2? dysregulation and activation of ER stress?mediated apoptotic pathways. These findings provide experimental evidence for elucidating the mechanisms of OSAHS-related neuronal injury and identifying potential therapeutic targets.
| [1] | KORKALAINEN H， LEPPANEN T， LEINO A， et al. Review and perspective on sleep-disordered breathing assessment in adults： Advances and clinical translation［J］. Sleep Med Rev， 2024， 72： 101874. |
| [2] | OGBU I， OGBU D， NWACHUKWU D， et al. Sleep-disordered breathing and neurocognitive disorders： Mechanisms and management［J］. J Clin Med， 2024， 13（17）： 5001. doi:10.3390/jcm13175001 |
| [3] | UNGVARI Z， FEKETE M， LEHOCZKI A， et al. Sleep disorders increase the risk of dementia， Alzheimer’s disease， and cognitive decline： A meta-analysis［J］. Gero Sci， 2025， 47： 4899-4920. doi:10.1007/s11357-025-01637-2 |
| [4] | El AMINE B， ARNAUD C， KHOURI C， et al. Cerebral oxidative stress， inflammation and apoptosis induced by intermittent hypoxia： Systematic review and meta-analysis of rodent data［J］. Eur Respir Rev， 2024， 33（173）： 240163. doi:10.1183/16000617.0162-2024 |
| [5] | MARTNEAU-DUSSAULT M-é， ANDRE C， DANEAULT V， et al. Medial temporal lobe and obstructive sleep apnea： Effects of sex， age， cognitive status， and free-water［J］. NeuroImage Clin， 2022， 36： 103235. doi:10.1016/j.nicl.2022.103235 |
| [6] | MARCHI NA， DANEAULT V， ANDRE C， et al. Altered fornix integrity is associated with sleep apnea-related hypoxemia in mild cognitive impairment［J］. Alzheimers Dement， 2024， 20（6）： 4092-4105. doi:10.1002/alz.13833 |
| [7] | LIN S， LIU Q， LIU S， et al. MRI-Indexed Perivascular Space Network Differences Between Obstructive and Central Sleep Apnea［J］. Radiology， 2024， 312（2）：e232274. |
| [8] | LAVALLE S， MASIELLO E， IANNELLA G， et al. Oxidative stress and inflammation biomarkers in OSA： A comprehensive review［J］. Life， 2024， 14（4）： 425. doi:10.3390/life14040425 |
| [9] | CHEN X， ZHANG L， HE Z， et al. Endoplasmic reticulum stress： Molecular mechanism and therapeutic potential［J］. Signal Transduct Target Ther， 2023， 8： 326. doi:10.1038/s41392-023-01570-w |
| [10] | MARTINEZ-VILLAR C， CALVO-GARCIA M， EULATE-BERAMENDI A， et al. Functional connectivity patterns in late-middle-aged men with obstructive sleep apnea［J］. Front Neurol， 2023， 14： 1215882. |
| [11] | MAKIO T， CHEN J， SIMMEN T. ER stress as a sentinel mechanism for ER Ca2? homeostasis［J］. Cell Calcium， 2024， 124： 102961. doi:10.1016/j.ceca.2024.102961 |
| [12] | YOU C， ZHANG Z， YING H，， et al. Blockage of calcium?sensing receptor ameliorates chronic intermittent hypoxia?induced cognitive impairment via the PERK?ATF4?CHOP pathway［J］. Exp Neurol， 2023， 368： 114500. doi:10.1016/j.expneurol.2023.114500 |
| [13] | WEN W， YAO Q， CHEN Y， et al. Transient receptor potential canonical 5 channel is involved in the cardiac damage related to obstructive sleep apnea-hypopnea syndrome in rats ［J］. Ann Palliat Med， 2020， 9（3）： 895-902. doi:10.21037/apm.2020.04.08 |
| [14] | 邱璇， 沙热扎提·依沙江， 陈玉岚， 等. 瞬时受体电位通道5对间歇性低氧致心肌焦亡的影响［J］. 实用医学杂志， 2024， 40（12）： 1637-1642. |
| [15] | ZHONG P， LI L， FENG X， et al. Neuronal ferroptosis and ferroptosis-mediated ER stress： Implications in cognitive dysfunction induced by chronic intermittent hypoxia in mice［J］. Int Immunopharmacol， 2024， 138： 112579. doi:10.1016/j.intimp.2024.112579 |
| [16] | QIU X， LI L， WEI J， et al. The protective role of Nrf2 on cognitive impairment in chronic intermittent hypoxia and sleep fragmentation mice［J］. Int Immunopharmacol， 2023， 116： 109813. doi:10.1016/j.intimp.2023.109813 |
| [17] | VARDANIAN M， RAVDIN L. Cognitive Complaints and Comorbidities in Obstructive Sleep Apnea［J］. leep Med Clin， 2022， 17（4）： 647-656. doi:10.1016/j.jsmc.2022.07.009 |
| [18] | ZHANG K， MA D， WU Y， et al. Impact of Chronic Intermittent Hypoxia on Cognitive Function and Hippocampal Neurons in Mice： A Study of Inflammatory and Oxidative Stress Pathways［J］. Nat Sci Sleep， 2024， 16： 2029-2043. doi:10.2147/nss.s489232 |
| [19] | MIYO K， UCHIDA Y， NAKANO R， et al. Intermittent Hypoxia Induces Cognitive Dysfunction and Hippocampal Gene Expression Changes in a Mouse Model of Obstructive Sleep Apnea［J］. Int J Mol Sci， 2025， 26（15）： 7495. doi:10.3390/ijms26157495 |
| [20] | JIA N N， GUO J， FENG J， et al. Chronic intermittent hypoxia–induced neural injury： Mechanisms and interventions［J］. CNS Neurosci Ther， 2025， 31（4）： e70384. |
| [21] | YANG H， YUAN Y， YANG K， et al. ELK4 ameliorates cognitive impairment and neuroinflammation induced by obstructive sleep apnea［J］. Brain Res Bull， 2024， 216： 111054. doi:10.1016/j.brainresbull.2024.111054 |
| [22] | YANG X， ZHANG Y， LIU H， et al. CaMKIIγ advances chronic intermittent hypoxia-induced cardiomyocyte apoptosis via HIF-1 signaling pathway［J］. Sleep Breath， 2025， 29（1）： 85. doi:10.1007/s11325-024-03225-8 |
| [23] | YOU Z， WANG X， SUN Q， et al. Blockage of calcium-sensing receptor improves chronic intermittent hypoxia-induced cognitive impairment by PERK-ATF4-CHOP pathway［J］. Exp Neurol， 2023， 370： 114518. doi:10.1016/j.expneurol.2023.114500 |
| [24] | YOU C， SUN Y， HE Z， et al. Blockage of calcium-sensing receptor improves chronic intermittent hypoxia-induced cognitive impairment by PERK–ATF4–CHOP pathway［J］. Exp Neurol， 2023， 367： 114489. doi:10.1016/j.expneurol.2023.114500 |
| [25] | MA N， LU H， LI N， et al. CHOP-mediated Gasdermin E expression promotes pyroptosis， inflammation， and mitochondrial damage in renal ischemia-reperfusion injury［J］. Cell Death Dis， 2024， 15（2）： 163. doi:10.1038/s41419-024-06525-9 |
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