Remote Ischemic Conditioning Attenuates Apoptosis, the Inflammatory Response, and Reperfusion Injury in Ischemic-Stroke Model Rats via the ELA-Apelin-APJ System.

Background: Remote ischemic conditioning (RIC), a novel neuroprotective therapy, has broad potential for reducing the occurrence and recurrence of cerebrovascular events, yet its mechanisms are not incompletely understood. The aim of this study is to investigate whether RIC alleviates apoptosis, inflammation, and reperfusion injury in rat models of ischemic stroke by regulating the Elabela (ELA)-apelin-Apelin receptor (APJ) system.

Methods: We established a rat model of middle cerebral artery occlusion (MCAO) with ischemia-reperfusion injury, and RIC was administered twice daily for 3 days post-MCAO. Cerebral infarct volume was measured and neuronal damage was assessed. Apoptosis-related caspase-3 expression was detected by Terminal deoxynucleotidyl Utransferase nick-End Labeling (TUNEL) and Western blotting (WB). WB was also used to measure apelin, signal transducer and activator of transcription 3 (STAT3), and p-STAT3 protein levels in infarcted brain tissue. ELA miRNA expression was evaluated. Immunofluorescence was used to detect hypoxia-inducible factor 1α (HIF-1α) and activating transcription factor 4 (ATF4) expression. Serum levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured using enzyme-linked immunosorbent assay (ELISA).

Results: RIC reduced the cerebral infarct volume and neuronal damage in MCAO rats. Compared with the MCAO group, the RIC-treated group (MCAO+RIC) presented significantly lower caspase-3, TNF-α, IL-1β, p-STAT3, HIF-1α, and ATF4 expression (p < 0.05), whereas STAT3 and ELA miRNA expression and apelin protein levels were increased (p < 0.05). While positively correlated with STAT3 expression, Elabela and apelin levels exhibited a negative correlation with caspase-3 (p < 0.05).

Conclusions: RIC mitigates MCAO-induced neuronal apoptosis, inflammation, and reperfusion injury by modulating the ELA-apelin-APJ system, highlighting its therapeutic potential for ischemic stroke.