Diabetes impairs the protective effects of sevoflurane postconditioning in the myocardium subjected to ischemia/ reperfusion injury in rats: important role of Drp1.

BACKGROUND

Sevoflurane postconditioning (SevP) effectively relieves myocardial ischemia/reperfusion (I/R) injury but performs poorly in the diabetic myocardium. Previous studies have revealed the important role of increased oxidative stress in diabetic tissues. Notably, mitochondrial fission mediated by dynamin-related protein 1 (Drp1) is an upstream pathway of reactive oxygen production. Whether the ineffectiveness of SevP in the diabetic myocardium is related to Drp1-dependent mitochondrial fission remains unknown. This study aimed to explore the important role of Drp1 in the diabetic myocardium and investigate whether Drp1 inhibition could restore the cardioprotective effect of SevP.

METHODS

In the first part of the study, adult male Sprague-Dawley rats were divided into 6 groups. Rats in the diabetic groups were fed with high-fat and high-sugar diets for 8 weeks and injected intraperitoneally with streptozotocin (35 mg/kg). Myocardial I/R was induced by 30 min of occlusion of the left anterior descending branch of the coronary artery followed by 120 min of reperfusion. SevP was applied by continuous inhalation of 2.5 % sevoflurane 1 min before reperfusion, which lasted for 10 min. In the second part of the study, we applied mdivi-1 to investigate whether Drp1 inhibition could restore the cardioprotective effect of SevP in the diabetic myocardium. The myocardial infarct size, mitochondrial ultrastructure, apoptosis index, SOD activity, MDA content, and Drp1 expression were detected.

RESULTS

TTC staining and TUNEL results showed that the myocardial infarct size and apoptosis index were increased in the diabetic myocardium. However, SevP significantly alleviated myocardial I/R injury in the normal myocardium but not in the diabetic myocardium. Additionally, we found an elevation in Drp1 expression, accompanied by more severe fission-induced structural damage and oxidative stress in the diabetic myocardium. Interestingly, we discovered that the beneficial effect of SevP was restored by mdivi-1, which significantly suppressed mitochondrial fission and oxidative stress.

CONCLUSIONS

Our study demonstrates the crucial role of mitochondrial fission dependent on Drp1 in the diabetic myocardium subjected to I/R, and strongly indicates that Drp1 inhibition may restore the cardioprotective effect of SevP in diabetic rats.