TGF-ss 3 Protects Neurons Against Intermittent Hypoxia-Induced Oxidative Stress and Apoptosis Through Activation of the Nrf-2/ KEAP1/HO-1 Pathway via Binding to TGF-ss RI

作者全名："Huang, Yinpei; Liu, Zhili; Wang, Xin; Li, Yaoxu; Liu, Lian; Li, Bing"

作者地址："[Huang, Yinpei; Liu, Zhili; Wang, Xin; Liu, Lian; Li, Bing] Chongqing Med Univ, Dept ENT, Affiliated Hosp 1, Chongqing 400016, Peoples R China; [Li, Yaoxu] Chongqing Med Univ, Dept Oral & Maxillofacial Surg, Affiliated Hosp 1, Chongqing 400016, Peoples R China"

通信作者："Li, B (通讯作者)，Chongqing Med Univ, Dept ENT, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：NEUROCHEMICAL RESEARCH

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000982072600001

JCR分区：Q2

影响因子：3.7

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Intermittent hypoxia; Cognitive impairment; TGF-ss 3; TGF-ss RI; Oxidative stress; Nrf-2

摘要："Intermittent hypoxia (IH) is the primary pathological manifestation of obstructive sleep apnea (OSA) and the main cause of OSA-induced cognitive impairment. Hippocampal neurons are considered to be critical cells affected by IH. Transforming growth factor-ss 3 (TGF-ss 3) is a cytokine with a neuroprotective effect, which plays a crucial role in resisting hypoxic brain injury, while its role in IH- induced neuronal injury is still unclear. Here, we aimed to clarify the mechanism of TGF-ss 3 protecting IH-exposed neurons by regulating oxidative stress and secondary apoptosis. Morris water maze results revealed that IH exposure was unable to affect the vision and motor ability of rats, but significantly affected their spatial cognition. Second-generation sequencing (RNA-seq) and subsequent experiments supported that IH decreased TGF-ss 3 expression and stimulated reactive oxygen species (ROS)-induced oxidative stress and apoptosis in rat hippocampus. In vitro, IH exposure significantly activated oxidative stress within HT-22 cells. Exogenous administration of Recombinant Human Transforming Growth Factor-ss 3 (rhTGF-ss 3) prevented ROS surge and secondary apoptosis in HT-22 cells caused by IH, while TGF-ss type receptor I (TGF-ss RI) inhibitor SB431542 blocked the neuroprotective effect of rhTGF-ss 3. Nuclear factor erythroid 2-related factor 2 (Nrf-2) is a transcription factor preserving intracellular redox homeostasis. rhTGF-ss 3 improved the nuclear translocation of Nrf-2 and activated downstream pathway. However, Nrf-2 inhibitor ML385 suppressed the activation of the Nrf-2 mechanism by rhTGF-3 and restored the effects of oxidative stress damage. These results indicate that TGF-ss 3 binding to TGF-ss RI activates the intracellular Nrf-2/KEAP1/HO-1 pathway, reduces ROS creation, and attenuates oxidative stress and apoptosis in IH-exposed HT-22 cells."

基金机构："Natural Science Foundation of Chongqing, China [2022NSCQ-MSX0935]"

基金资助正文："This work was supported by the Natural Science Foundation of Chongqing, China [Grant Number 2022NSCQ-MSX0935]"