Inhibition of the Activating Transcription Factor 6 Branch of Endoplasmic Reticulum Stress Ameliorates Brain Injury after Deep Hypothermic Circulatory Arrest
Neurological dysfunction is a common complication of deep hypothermic circulatory arrest (DHCA). Endoplasmic reticulum (ER) stress plays a role in neuronal ischemia-reperfusion injury; however, it is unknown whether it contributes to DHCA-induced brain injury. Here, we aimed to investigate the role...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/12/3/814 |
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| author | You-Peng Zhang Qin Yang Yi-Ai Li Ming-Huan Yu Guo-Wei He Yu-Xiang Zhu Zhi-Gang Liu Xiao-Cheng Liu |
| author_facet | You-Peng Zhang Qin Yang Yi-Ai Li Ming-Huan Yu Guo-Wei He Yu-Xiang Zhu Zhi-Gang Liu Xiao-Cheng Liu |
| author_sort | You-Peng Zhang |
| collection | DOAJ |
| description | Neurological dysfunction is a common complication of deep hypothermic circulatory arrest (DHCA). Endoplasmic reticulum (ER) stress plays a role in neuronal ischemia-reperfusion injury; however, it is unknown whether it contributes to DHCA-induced brain injury. Here, we aimed to investigate the role of ER stress in a rat DHCA model and cell hypothermic oxygen–glucose deprivation reoxygenation (OGD/R) model. ER stress and apoptosis-related protein expression were identified using Western blot analysis. Cell counting assay-8 and flow cytometry were used to determine cell viability and apoptosis, respectively. Brain injury was evaluated using modified neurological severity scores, whereas brain injury markers were detected through histological examinations and immunoassays. We observed significant ER stress molecule upregulation in the DHCA rat hippocampus and in hypothermic OGD/R PC-12 cells. In vivo and in vitro experiments showed that ER stress or activating transcription factor 6 (ATF6) inhibition alleviated rat DHCA-induced brain injury, increased cell viability, and decreased apoptosis accompanied by C/EBP homologous protein (CHOP). ER stress is involved in DHCA-induced brain injury, and the inhibition of the ATF6 branch of ER stress may ameliorate this injury by inhibiting CHOP-mediated apoptosis. This study establishes a scientific foundation for identifying new therapeutic targets for perioperative brain protection in clinical DHCA. |
| first_indexed | 2024-03-11T09:38:45Z |
| format | Article |
| id | doaj.art-38b036cdc4bf465c8241bd5d5c123332 |
| institution | Directory Open Access Journal |
| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-11T09:38:45Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Clinical Medicine |
| spelling | doaj.art-38b036cdc4bf465c8241bd5d5c1233322023-11-16T17:07:34ZengMDPI AGJournal of Clinical Medicine2077-03832023-01-0112381410.3390/jcm12030814Inhibition of the Activating Transcription Factor 6 Branch of Endoplasmic Reticulum Stress Ameliorates Brain Injury after Deep Hypothermic Circulatory ArrestYou-Peng Zhang0Qin Yang1Yi-Ai Li2Ming-Huan Yu3Guo-Wei He4Yu-Xiang Zhu5Zhi-Gang Liu6Xiao-Cheng Liu7Center for Basic Medical Research, Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, 61 Third Street, Tianjin 300000, ChinaCenter for Basic Medical Research, Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, 61 Third Street, Tianjin 300000, ChinaCenter for Basic Medical Research, Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, 61 Third Street, Tianjin 300000, ChinaCenter for Basic Medical Research, Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, 61 Third Street, Tianjin 300000, ChinaCenter for Basic Medical Research, Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, 61 Third Street, Tianjin 300000, ChinaCenter for Basic Medical Research, Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, 61 Third Street, Tianjin 300000, ChinaCenter for Basic Medical Research, Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, 61 Third Street, Tianjin 300000, ChinaCenter for Basic Medical Research, Department of Cardiovascular Surgery, TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Graduate School of Peking Union Medical College, 61 Third Street, Tianjin 300000, ChinaNeurological dysfunction is a common complication of deep hypothermic circulatory arrest (DHCA). Endoplasmic reticulum (ER) stress plays a role in neuronal ischemia-reperfusion injury; however, it is unknown whether it contributes to DHCA-induced brain injury. Here, we aimed to investigate the role of ER stress in a rat DHCA model and cell hypothermic oxygen–glucose deprivation reoxygenation (OGD/R) model. ER stress and apoptosis-related protein expression were identified using Western blot analysis. Cell counting assay-8 and flow cytometry were used to determine cell viability and apoptosis, respectively. Brain injury was evaluated using modified neurological severity scores, whereas brain injury markers were detected through histological examinations and immunoassays. We observed significant ER stress molecule upregulation in the DHCA rat hippocampus and in hypothermic OGD/R PC-12 cells. In vivo and in vitro experiments showed that ER stress or activating transcription factor 6 (ATF6) inhibition alleviated rat DHCA-induced brain injury, increased cell viability, and decreased apoptosis accompanied by C/EBP homologous protein (CHOP). ER stress is involved in DHCA-induced brain injury, and the inhibition of the ATF6 branch of ER stress may ameliorate this injury by inhibiting CHOP-mediated apoptosis. This study establishes a scientific foundation for identifying new therapeutic targets for perioperative brain protection in clinical DHCA.https://www.mdpi.com/2077-0383/12/3/814apoptosisATF6brain injurydeep hypothermic circulatory arrestendoplasmic reticulum stress |
| spellingShingle | You-Peng Zhang Qin Yang Yi-Ai Li Ming-Huan Yu Guo-Wei He Yu-Xiang Zhu Zhi-Gang Liu Xiao-Cheng Liu Inhibition of the Activating Transcription Factor 6 Branch of Endoplasmic Reticulum Stress Ameliorates Brain Injury after Deep Hypothermic Circulatory Arrest Journal of Clinical Medicine apoptosis ATF6 brain injury deep hypothermic circulatory arrest endoplasmic reticulum stress |
| title | Inhibition of the Activating Transcription Factor 6 Branch of Endoplasmic Reticulum Stress Ameliorates Brain Injury after Deep Hypothermic Circulatory Arrest |
| title_full | Inhibition of the Activating Transcription Factor 6 Branch of Endoplasmic Reticulum Stress Ameliorates Brain Injury after Deep Hypothermic Circulatory Arrest |
| title_fullStr | Inhibition of the Activating Transcription Factor 6 Branch of Endoplasmic Reticulum Stress Ameliorates Brain Injury after Deep Hypothermic Circulatory Arrest |
| title_full_unstemmed | Inhibition of the Activating Transcription Factor 6 Branch of Endoplasmic Reticulum Stress Ameliorates Brain Injury after Deep Hypothermic Circulatory Arrest |
| title_short | Inhibition of the Activating Transcription Factor 6 Branch of Endoplasmic Reticulum Stress Ameliorates Brain Injury after Deep Hypothermic Circulatory Arrest |
| title_sort | inhibition of the activating transcription factor 6 branch of endoplasmic reticulum stress ameliorates brain injury after deep hypothermic circulatory arrest |
| topic | apoptosis ATF6 brain injury deep hypothermic circulatory arrest endoplasmic reticulum stress |
| url | https://www.mdpi.com/2077-0383/12/3/814 |
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