Effects of Sitagliptin on myocardial remodeling and autophagy in diabetic mice and its mechanism

Abstract

Objective: To investigate the effects of Sitagliptin on myocardial remodeling and autophagy in diabetic mice and its possible mechanisms. Methods: C57 mice aged ten weeks were treated with streptozocin (STZ) at the dose of 50 mg/(kg·d) by intraperitoneal injections for five consecutive days, and the level of fasting blood glucose concentration was higher than 16.7 mmol/l after seven days indicated that the diabetic model was established successfully. Mice were divided into four groups, including control group (n=10) which was intraperitoneally injected with the same volum of saline, the model group (n=8), Sitagliptin treatment group(diabetic mice were treated with Sitagliptin at the dose of 10 mg/(kg·d)by gavage, n=8) and the inhibitor group(diabetic mice were treated with Compound C, an AMPK inhibitor, at the dose of 10 mg/(kg·d) by intraperitoneal injection, n=8). After six weeks, all the mices were weighted and then put to death and the hearts were separated to caculate ventricular /body weight ratio. Hemaloxylin-Eosin (HE) staining was used to observe the cell morphology and masson staining was used to observe interstitial fibrosis. Western blot was used to test the heart protein expressions of Connexin43(Cx43), adenosine 5'-monophosphate -activated protein kinase (AMPK), brain natriuretic peptide(BNP), transforming growth factor(TGF-β) and LC3B. Results: After six weeks of treatment, compared with control group, the ventricular /body weight ratio was improved (P＜0.05), The cardiomyocyte hypertrophy and increased fibrosis were observed in the model group. The expression levels of BNP and TGF-β were increased, while the expression levels of Cx43,LC3B and AMPK were decreased significantly(P＜0.05). However, compared with model group, treatment with Sitagliptin decreased BNP, TGF-β protein levels and increased Cx43 and LC3B protein levels, while Compound C could inhibit the upregulation of Cx43, LC3B and AMPK protein (P＜0.05). Conclusion: Sitagliptin could improve cardiac hypertrophy and decrease interstitial fibrosis and AMPK-related signaling pathways was involved in the regulation of Cx43 and autophagy.