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.
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.
['Xu|Weilin|W|', 'Li|Tao|T|', 'Gao|Liansheng|L|', 'Zheng|Jingwei|J|', 'Yan|Jun|J|', 'Zhang|Jianmin|J|', 'Shao|Anwen|A|http://orcid.org/0000-0001-9986-6290']
D055372:AMP-Activated Protein Kinases D000818:Animals D000075244:Apelin Receptors D001930:Brain Injuries D018797:Cell Cycle Proteins D004305:Dose-Response Relationship, Drug D059865:Endoplasmic Reticulum Stress D036341:Intercellular Signaling Peptides and Proteins D008297:Male D000071199:NLR Family, Pyrin Domain-Containing 3 Protein D018384:Oxidative Stress D011485:Protein Binding D051381:Rats D017207:Rats, Sprague-Dawley D013345:Subarachnoid Hemorrhage
Apelin-13 APJ Early brain injury NLRP3 Oxidative stress Neuroinflammation SAH