Journal Article

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

Xu, Weilin, Li, Tao, Zheng, Jingwei, Zhang, Jianmin, Gao, Liansheng, Yan, Jun, Shao, Anwen

2019

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenosine kinase / Adenosine monophosphate / AMP / AMP-Activated Protein Kinases - metabolism / Aneurysms / Animals / Apelin Receptors - metabolism / Apelin-13 / APJ / Apoptosis / Biomedical and Life Sciences / Biomedicine / Blood-brain barrier / Brain injuries / Brain Injuries - metabolism / Brain Injuries - prevention & control / Brain injury / Carotid arteries / Caspase-1 / Cell Cycle Proteins - metabolism / Cerebral edema / Dose-Response Relationship, Drug / Early brain injury / Edema / Endoplasmic reticulum / Endoplasmic Reticulum Stress - drug effects / Endoplasmic Reticulum Stress - physiology / Enzyme inhibitors / Experiments / Fluorescent antibody technique / Hemorrhage / Immunofluorescence / Immunology / Inflammasomes / Inflammation / Intercellular Signaling Peptides and Proteins - metabolism / Intercellular Signaling Peptides and Proteins - pharmacology / Intercellular Signaling Peptides and Proteins - therapeutic use / Kinases / Laboratory animals / Male / Microglia / Neurobiology / Neuroinflammation / Neurology / Neuroprotection / Neurosciences / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Oxidative stress / Oxidative Stress - drug effects / Oxidative Stress - physiology / Peroxidase / Protein Binding - physiology / Protein kinase / Protein kinases / Proteins / Pyrin protein / Rats / Rats, Sprague-Dawley / Reactive oxygen species / SAH / Signal transduction / siRNA / Spatial discrimination learning / Spatial memory / Stroke / Subarachnoid hemorrhage / Subarachnoid Hemorrhage - drug therapy / Subarachnoid Hemorrhage - metabolism / Thioredoxin / Thioredoxins / Traumatic brain injury / Tumor necrosis factor-α / Veins & arteries / Water content / Western blotting