Exendin-4, a glucagon-like peptide-1 receptor agonist, inhibits hyperglycemia-induced apoptosis in myocytes by suppressing receptor for advanced glycation end products expression

Activation of the receptor for advanced glycation end products (RAGE) axis may have an important role in apoptosis. Glucagon-like peptide-1 (GLP-1) is a gut hormone that has been proposed as a therapeutic target for the treatment of diabetes, and GLP-1 receptor agonists have been reported to protect against myocardial injury associated with diabetes. The aim of the present study was to investigate the cardioprotective mechanism of exendin-4 (EX-4), a GLP-1 receptor agonist, against myocardial cell apoptosis induced by hyperglycemia. Neonatal rat ventricular myocytes were prepared by enzymatic dissociation and then cultured with high levels of glucose (HG) in the presence or absence of EX-4. Cell apoptosis was detected using an annexin V-fluorescein isothiocyanate/propidium iodide kit, and cell viability was measured using an MTT assay. RAGE expression levels and the activity of caspase-3 were assessed by western blot analysis. The results demonstrated that the incubation of myocytes with HG led to a time-dependent activation of RAGE, and the protein expression of RAGE was increased at 6 h and peaked at 24 h (P<0.05). Hyperglycemia was also found to significantly decrease cell viability and increase apoptosis (P<0.05). In addition, EX-4 significantly inhibited hyperglycemia-induced RAGE expression and the apoptosis of myocytes, and improved cell viability in a dose-dependent manner (P<0.05). When the concentration of EX-4 was 10 nM, the myocardial cell viability was significantly improved, and the levels of RAGE expression and apoptosis were significantly decreased compared with those in the HG group in the absence of EX-4 (P<0.05). Therefore, the results from the present study suggest that the cardioprotective effect induced by EX-4, a GLP-1 receptor agonist, against diabetic cardiomyopathy may be associated with the inhibition of RAGE expression.