Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Yu J

PROVIDER: S-EPMC7885510 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Yu Jing J He Jiandong J Yang Wenqu W Wang Xiang X Shi Gaoxiang G Duan Yinglei Y Wang Hui H Han Chongfang C

BMC cardiovascular disorders 20210216 1

<h4>Background</h4>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 mitochon ...[more]

PMID: 33593294

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Project description:Toll-like receptor 2 (TLR2)-mediated myocardial inflammation serves an important role in promoting myocardial ischemic/reperfusion (I/R) injury. Previous studies have shown that miR?499 is critical for cardioprotection after ischemic postconditioning (IPostC). Therefore, the present study evaluated the protective effect of IPostC on the myocardium by inhibiting TLR2, and also assessed the involvement of microRNA (miR)?499. Rat hearts were subjected to 30 min of ischemia and 2 h of reperfusion. The IPostC was 3 cycles of 30 sec of reperfusion and 30 sec of re?occlusion prior to reperfusion. In total, 90 rats were randomly divided into six groups (n=15 per group): Sham; I/R; IPostC; miR?499 negative control adeno?associated virus (AAV) vectors + IPostC; miR?499 inhibitor AAV vectors + IPostC; and miR?499 mimic AAV vectors + IPostC. It was identified that IPostC significantly decreased the I/R?induced cardiomyocyte apoptotic index (29.4±2.03% in IPostC vs. 42.64±2.27% in I/R; P<0.05) and myocardial infarct size (48.53±2.49% in IPostC vs. 66.52±3.1% in I/R; P<0.05). Moreover, these beneficial effects were accompanied by increased miR?499 expression levels (as demonstrated by reverse transcription?quantitative PCR) in the myocardial tissue and decreased TLR2, protein kinase C (PKC), interleukin (IL)?1? and IL?6 expression levels (as demonstrated by western blotting and ELISA) in the myocardium and serum. The results indicated that IPostC + miR?499 mimics significantly inhibited inflammation and the PKC signaling pathway and enhanced the anti?inflammatory and anti?apoptotic effects of IPostC. However, IPostC + miR?499 inhibitors had the opposite effect. Therefore, it was speculated that IPostC may have a miR?499?dependent cardioprotective effect. The present results suggested that miR?499 may be involved in IPostC?mediated ischemic cardioprotection, which may occur via local and systemic TLR2 inhibition, subsequent inhibition of the PKC signaling pathway and a decrease in inflammatory cytokine release, including IL?1? and IL?6. Moreover, these effects will ultimately lead to a decrease in the myocardial apoptotic index and myocardial infarct size via the induction of the anti?apoptotic protein Bcl?2, and inhibition of the pro?apoptotic protein Bax in myocardium.

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Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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