Urocortin ameliorates diabetic cardiomyopathy in rats via the Akt/GSK-3β signaling pathway

Urocortin has been shown to exert powerful protective effects on various cardiovascular disease models. However, the role and mechanism of urocortin in protecting against diabetic cardiomyopathy (DCM) has not yet been elucidated. In the present study, the effects of urocortin on cardiac dysfunction, fibrosis, inflammation and the interrelated signaling pathways were investigated in a diabetic rat model. Diabetes mellitus (DM) was induced in the rats by intraperitoneal injection of streptozotocin. The diabetic rats were randomly divided into four groups: Diabetic control, urocortin, urocortin + astressin treatment and urocortin + triciribine treatment groups. All the experiments were conducted at 16 weeks following the induction of DM. The levels of glycosylated hemoglobin (HbA1c), creatine phosphokinase isoenzyme (CK-MB) and plasma brain natriuretic peptide (BNP), as well as the myocardial collagen volume fraction (CVF) and left ventricular mass index (LVWI), were measured. In addition, levels of inflammatory factors, including transforming growth factor (TGF)-beta 1, connective tissue growth factor (CTGF) and interrelated proteins, such as Akt and glycogen synthase kinase (GSK)-3 beta, were detected by biochemical analyses. In the diabetic group, the levels of BNP and CK-MB, as well as the mRNA and protein expression levels of TGF-beta 1 and CTGF, and the LVWI and CVF, were higher compared with the rats in the control group (P<0.05). This was accompanied by decreased Akt and GSK-3 beta phosphorylation (P<0.05). Notably, urocortin attenuated myocardial dysfunction, cardiac fibrosis and inflammation in the hearts of the diabetic rats. However, urocortin exhibited no effect on the level of HbA1c. In addition, the inhibited phosphorylation of Akt and GSK-3 beta was restored with urocortin administration. However, all the effects of urocortin were eliminated with treatment of the corticotropin releasing factor receptor 2 antagonist, astressin. Triciribine, an Akt inhibitor, partially eliminated the effects of urocortin on myocardial dysfunction, inflammation and cardiac fibrosis in the hearts of the diabetic rats. These results indicated that urocortin may exhibit great therapeutic potential in the treatment of DCM by attenuating fibrosis and inflammation. Furthermore, the Akt/GSK-3 beta signaling pathway may be partially involved in mediating these effects.