Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats
Abstract Background Neuroinflammation and oxidative stress play important roles in early brain injury following subarachnoid hemorrhage (SAH). This study is the first to show that activation of apelin receptor (APJ) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-associated inflammation...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-019-1620-3 |
| _version_ | 1818384745080291328 |
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| author | Weilin Xu Tao Li Liansheng Gao Jingwei Zheng Jun Yan Jianmin Zhang Anwen Shao |
| author_facet | Weilin Xu Tao Li Liansheng Gao Jingwei Zheng Jun Yan Jianmin Zhang Anwen Shao |
| author_sort | Weilin Xu |
| collection | DOAJ |
| description | Abstract Background Neuroinflammation and oxidative stress play important roles in early brain injury following subarachnoid hemorrhage (SAH). This study is the first to show that activation of apelin receptor (APJ) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-associated inflammation and oxidative stress after SAH. Methods Apelin-13, apelin siRNA, APJ siRNA, and adenosine monophosphate-activated protein kinase (AMPK) inhibitor-dorsomorphin were used to investigate if the activation of APJ could provide neuroprotective effects after SAH. Brain water content, neurological functions, blood-brain barrier (BBB) integrity, and inflammatory molecules were evaluated at 24 h after SAH. Western blotting and immunofluorescence staining were applied to assess the expression of target proteins. Results The results showed that endogenous apelin, APJ, and p-AMPK levels were significantly increased and peaked in the brain 24 h after SAH. In addition, administration of exogenous apelin-13 significantly alleviated neurological functions, attenuated brain edema, preserved BBB integrity, and also improved long-term spatial learning and memory abilities after SAH. The underlying mechanism of the neuroprotective effects of apelin-13 is that it suppresses microglia activation, prevents ER stress from overactivation, and reduces the levels of thioredoxin-interacting protein (TXNIP), NOD-like receptor pyrin domain-containing 3 protein (NLRP3), Bip, cleaved caspase-1, IL-1β, TNFα, myeloperoxidase (MPO), and reactive oxygen species (ROS). Furthermore, the use of APJ siRNA and dorsomorphin abolished the neuroprotective effects of apelin-13 on neuroinflammation and oxidative stress. Conclusions Exogenous apelin-13 binding to APJ attenuates early brain injury by reducing ER stress-mediated oxidative stress and neuroinflammation, which is at least partly mediated by the AMPK/TXNIP/NLRP3 signaling pathway. |
| first_indexed | 2024-12-14T03:27:08Z |
| format | Article |
| id | doaj.art-8fd45ea0fe114d6d967a77bd09a4a5bb |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-14T03:27:08Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-8fd45ea0fe114d6d967a77bd09a4a5bb2022-12-21T23:18:51ZengBMCJournal of Neuroinflammation1742-20942019-12-0116111410.1186/s12974-019-1620-3Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in ratsWeilin Xu0Tao Li1Liansheng Gao2Jingwei Zheng3Jun Yan4Jianmin Zhang5Anwen Shao6Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Neurosurgery, Affiliated Tumor Hospital of Guangxi Medical UniversityDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang UniversityDepartment of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang UniversityAbstract Background Neuroinflammation and oxidative stress play important roles in early brain injury following subarachnoid hemorrhage (SAH). This study is the first to show that activation of apelin receptor (APJ) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-associated inflammation and oxidative stress after SAH. Methods Apelin-13, apelin siRNA, APJ siRNA, and adenosine monophosphate-activated protein kinase (AMPK) inhibitor-dorsomorphin were used to investigate if the activation of APJ could provide neuroprotective effects after SAH. Brain water content, neurological functions, blood-brain barrier (BBB) integrity, and inflammatory molecules were evaluated at 24 h after SAH. Western blotting and immunofluorescence staining were applied to assess the expression of target proteins. Results The results showed that endogenous apelin, APJ, and p-AMPK levels were significantly increased and peaked in the brain 24 h after SAH. In addition, administration of exogenous apelin-13 significantly alleviated neurological functions, attenuated brain edema, preserved BBB integrity, and also improved long-term spatial learning and memory abilities after SAH. The underlying mechanism of the neuroprotective effects of apelin-13 is that it suppresses microglia activation, prevents ER stress from overactivation, and reduces the levels of thioredoxin-interacting protein (TXNIP), NOD-like receptor pyrin domain-containing 3 protein (NLRP3), Bip, cleaved caspase-1, IL-1β, TNFα, myeloperoxidase (MPO), and reactive oxygen species (ROS). Furthermore, the use of APJ siRNA and dorsomorphin abolished the neuroprotective effects of apelin-13 on neuroinflammation and oxidative stress. Conclusions Exogenous apelin-13 binding to APJ attenuates early brain injury by reducing ER stress-mediated oxidative stress and neuroinflammation, which is at least partly mediated by the AMPK/TXNIP/NLRP3 signaling pathway.https://doi.org/10.1186/s12974-019-1620-3Early brain injurySAHNeuroinflammationOxidative stressApelin-13APJ |
| spellingShingle | Weilin Xu Tao Li Liansheng Gao Jingwei Zheng Jun Yan Jianmin Zhang Anwen Shao Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats Journal of Neuroinflammation Early brain injury SAH Neuroinflammation Oxidative stress Apelin-13 APJ |
| title | Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats |
| title_full | Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats |
| title_fullStr | Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats |
| title_full_unstemmed | Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats |
| title_short | Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats |
| title_sort | apelin 13 apj system attenuates early brain injury via suppression of endoplasmic reticulum stress associated txnip nlrp3 inflammasome activation and oxidative stress in a ampk dependent manner after subarachnoid hemorrhage in rats |
| topic | Early brain injury SAH Neuroinflammation Oxidative stress Apelin-13 APJ |
| url | https://doi.org/10.1186/s12974-019-1620-3 |
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