Inhibition of inflammation and apoptosis through the cyclic GMP‐AMP synthase‐stimulator of interferon genes pathway by stress granules after ALKBH5 demethylase activation during diabetic myocardial ischaemia‐reperfusion injury

Abstract Aim Post‐transcriptional modifications and their specific mechanisms are the focus of research on the regulation of myocardial damage. Stress granules (SGs) can inhibit the inflammatory response by inhibiting the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway. This study investigated whether alkylation repair homologue protein 5 (ALKBH5) could affect myocardial inflammation and apoptosis during diabetic myocardial ischaemia‐reperfusion injury (IRI) through the cGAS‐STING pathway via SGs. Methods A diabetes ischaemia‐reperfusion rat model and a high glucose hypoxia/reoxygenation cell model were established. Adeno‐associated virus (AAV) and lentivirus (LV) were used to overexpress ALKBH5, while the SG agonist arsenite (Ars) and the SG inhibitor anisomycin were used as interventions. Then, the levels of apoptosis and related indicators in the cell and rat models were measured. Results In the in vivo experiment, compared with the normal sham group, the degree of myocardial tissue damage, creatine kinase‐MB and cardiac troponin I in serum, and myocardial apoptosis, the infarcted area of myocardium, and the level of B‐cell lymphoma 2 associated X protein, cGAS‐STING pathway and inflammatory factors in the diabetes ischaemia‐reperfusion group were significantly increased. However, the expression of SGs and the levels of ALKBH5, rat sarcoma‐GTPase‐activating protein‐binding protein 1, T‐cell intracellular antigen‐1 and Bcl2 were significantly decreased. After AAV‐ALKBH5 intervention, the degree of myocardial tissue damage, degree of myocardial apoptosis, and extent of myocardial infarction in myocardial tissue were significantly decreased. In the in vitro experiment, compared with those in the normal control group, the levels of lactate dehydrogenase, inflammation and apoptosis were significantly greater, and cell viability and the levels of ALKBH5 and SGs were decreased in the high glucose and hypoxia/reoxygenation groups. In the high glucose hypoxia/reoxygenation cell model, the degree of cell damage, inflammation, and apoptosis was greater than those in the high glucose and hypoxia/reoxygenation models, and the levels of ALKBH5 and SGs were further decreased. LV‐ALKBH5 and Ars alleviated the degree of cell damage and inhibited inflammation and cell apoptosis. The inhibition of SGs could partly reverse the protective effect of LV‐ALKBH5. The cGAS agonist G140 antagonized the inhibitory effects of the SG agonist Ars on cardiomyocyte apoptosis, inflammation and the cGAS‐STING pathway. Conclusion Both ALKBH5 and SGs inhibited myocardial inflammation and apoptosis during diabetic myocardial ischaemia‐reperfusion. Mechanistically, ALKBH5 might inhibit the apoptosis of cardiomyocytes by promoting the expression of SGs through the cGAS‐STING pathway.