Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin ameliorates inflammation and autophagy in mice hindlimb ischemia–reperfusion injury

Abstract

Abstract Background Ischemia-reperfusion injury (I/R) for skeletal muscle usually results from vascular injuries or trauma. Sitagliptin (STG) is an effective member of the dipeptidyl peptidase-4 (DPP-4) inhibitors drug family that plays roles in oxidative stress regulation, inflammation, and autophagy control. In this study, we evaluated the protective roles of STG against I/R of gastrocnemius muscle and the underlying mechanisms. Materials and methods Forty-eight mice were randomly allocated into three groups: Group I (n = 24): control group which was subdivided equally into subgroup IA; negative control, subgroup IB; sitagliptin (STG), Group II (n = 12): ischemia–reperfusion injury (I/R), and Group III (n = 12): sitagliptin pretreatment (300 mg/kg/ day; p.o.) for two weeks followed by ischemia–reperfusion injury (STG + I/R). We measured SOD activity and MDA level to assess oxidative stress. Moreover, GLP-1/p-PI3K/ p-AKT expression levels were investigated. Autophagy was estimated by assessing lncRNA H19, Beclin-1 and ATG7 expression by RT-qPCR analysis. Inflammatory markers were assessed by iNOS and NF‐κB expression using immunohistochemistry. Results Our results revealed that STG pretreatment significantly attenuated oxidative stress and inflammation and upregulated GLP-1, p-PI3K, and p-AKT protein levels. Also, LnRNA H19, Becline-1, and ATG7 mRNA expression were downregulated as well as decrease the expression of the inflammatory markers iNOS and NF‐κB with STG pretreatment. Conclusion Our results highlighted the useful effects of Sitagliptin during hind limb I/R that could be mediated by antioxidant, anti-inflammatory effects, and attenuation of excessive autophagy.

Keywords

• Ischemia–reperfusion injury
• LnRNAH19
• Autophagy
• Sitagliptin
• ATG7