PM_2.5-Induced Cardiac Structural Modifications and Declined Pro-Survival Signalling Pathways Are Responsible for the...

Circulatory GSK3β is recognized as a biomarker and therapeutic target for diseases, including myocardial diseases. However, its potential as a target for myocardial ischemia-reperfusion injury (IR) in the presence of PM_2.5 exposure is unclear. Wistar rats underwent IR following either a 21-day or single exposure to PM_2.5 at a concentration of 250 µg/m³. The effects of GSK3β inhibitor on cardiac physiology, tissue injury, mitochondrial function, and the PI3K/AKT/GSK3β signalling axis were examined. The inhibitor was not effective in improving hemodynamics or reducing IR-induced infarction in the myocardium exposed to PM_2.5 for 21 days. However, for a single-day exposure, the inhibitor showed potential in mitigating cardiac injury. In normal hearts undergoing IR, the inhibitor activated the PI3K/AKT signalling pathway, improved mitochondrial function, and reduced oxidative stress. These positive effects were not observed in PM_2.5-exposed rats. Furthermore, the inhibitor stimulated autophagy in hearts exposed to PM_2.5 for 21 days and subjected to IR, resulting in increased mTOR expression and decreased AMPK expression. In normal hearts and those exposed to a single dose of PM_2.5, the inhibitor effectively activated the PI3K/Akt/AMPK axis. These findings suggest that GSK3β may not be a reliable therapeutic target for IR in the presence of chronic PM_2.5 exposure.