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. 2017 Feb 7;16(1):19.
doi: 10.1186/s12933-017-0501-2.

Inhibition of dynamin-related protein 1 protects against myocardial ischemia-reperfusion injury in diabetic mice

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Inhibition of dynamin-related protein 1 protects against myocardial ischemia-reperfusion injury in diabetic mice

Mingge Ding et al. Cardiovasc Diabetol. .

Erratum in

Abstract

Background: Many cardioprotective pharmacological agents failed to exert their protective effects in diabetic hearts subjected to myocardial ischemia/reperfusion (MI/R). Identify the molecular basis linking diabetes with MI/R injury is scientifically important and may provide effective therapeutic approaches. Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays an important role in MI/R injury under non-diabetic conditions. Importantly, recent studies indicated that Drp1-mediated mitochondrial fission is enhanced in the myocardium of diabetic mice. The above evidences suggested that Drp1 may be one critical molecule linking diabetes with MI/R injury. We hypothesized that inhibition of Drp1 may be effective to reduce MI/R injury in diabetic hearts.

Methods: High-fat diet and streptozotocin-induced diabetic mice were subjected to MI/R or sham operation. Mdivi-1 (1.2 mg/kg), a small molecule inhibitor of Drp1 or vehicle was administrated 15 min before the onset of reperfusion. Outcome measures included mitochondrial morphology, mitochondrial function, myocardial injury, cardiac function and oxidative stress.

Results: Mitochondrial fission was significantly increased following MI/R as evidenced by enhanced translocation of Drp1 to mitochondria and decreased mitochondrial size. Delivery of Mdivi-1 into diabetic mice markedly inhibited Drp1 translocation to the mitochondria and reduced mitochondrial fission following MI/R. Inhibition of Drp1 in diabetic hearts improved mitochondrial function and cardiac function following MI/R. Moreover, inhibition of Drp1 reduced myocardial infarct size and serum cardiac troponin I and lactate dehydrogenase activities. These cardioprotective effects were associated with decreased cardiomyocyte apoptosis and malondialdehyde production and increased activities of antioxidant enzyme manganese superoxide dismutase.

Conclusions: Pharmacological inhibition of Drp1 prevents mitochondrial fission and reduces MI/R injury in diabetic mice. The findings suggest Drp1 may be a potential novel therapeutic target for diabetic cardiac complications.

Keywords: Diabetes; Drp1; Ischemia–reperfusion; Mitochondrial fission.

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Figures

Fig. 1
Fig. 1
Schematic representation of experimental protocol. Male C57 mice were fed with HFD for 4 weeks and then injected with streptozotocin (STZ) at the dose of 90 mg/kg intraperitoneally. One week after STZ injection, mice were considered to have developed diabetes only if their 12-h fasting blood glucose levels were higher than 11.1 mmol/L. The diabetic mice were subjected to 30 min ischemia followed by 3 h reperfusion (for determination of mitochondrial dynamics, mitochondrial function, myocardial apoptosis and ROS) or 24 h reperfusion (for determination of infarct size and cardiac function). Mdivi-1 (1.2 mg/kg) or vehicle (dimethyl sulfoxide) was administrated intraperitoneally 15 min before the onset of myocardial reperfusion
Fig. 2
Fig. 2
Mdivi-1 inhibited Drp1 translocation to the mitochondria and prevented mitochondrial fission following MI/R in diabetic mice. a Total Drp1 expression. b Mitochondrial Drp1 expression. c Number of mitochondria per μm2 in each field of view. d Representative transmission electron microscopic images (major finding is c, e). e Percentage of mitochondria that sorted into three size categories based on area. MI/R group means diabetic mice subjected to MI/R and vehicle (dimethyl sulfoxide) administration. Values are mean ± SEM. N = 3–6 hearts for each group. *P < 0.05, **P < 0.01 vs. Sham. # P < 0.05, ## P < 0.01 vs. MI/R
Fig. 3
Fig. 3
Mdivi-1 improved mitochondrial function in diabetic mice subjected to MI/R. a Complex I activity. b Complex II activity. c Complex III activity. d Complex IV activity. e ATP content. MI/R group means diabetic mice subjected to MI/R and vehicle (dimethyl sulfoxide) administration. Values are mean ± SEM. N = 8 hearts for each group. **P < 0.01 vs. Sham. # P < 0.05, ## P < 0.01 vs. MI/R
Fig. 4
Fig. 4
Mdivi-1 improved cardiac function in diabetic mice subjected to MI/R. a Representative echocardiography images. b Left ventricular ejection fraction (LVEF). c Left ventricular end-systolic volume (LVESV). d Left ventricular end-diastolic volume (LVEDV). (E and F) ± LV dp/dt max, the instantaneous first derivation of left ventricle pressure. MI/R group means diabetic mice subjected to MI/R and vehicle (dimethyl sulfoxide) administration. Values are mean ± SEM. N = 8 animals for each group. **P < 0.01 vs. Sham. # P < 0.05, ## P < 0.01 vs. MI/R
Fig. 5
Fig. 5
Mdivi-1 reduced myocardial ischemia/reperfusion (MI/R) injury in diabetic mice. a Serum levels of cardiac troponin I (cTnI). b Serum levels of lactate dehydrogenase (LDH). c Representative images of myocardial infarct size stained by Evans blue and TTC. d Myocardial infarct size presented as percentage of infarct area (INF)/area at risk (AAR). MI/R group means diabetic mice subjected to MI/R and vehicle (dimethyl sulfoxide) administration. Values are mean ± SEM. N = 8 animals for each group. **P < 0.01 vs. Sham. ## P < 0.01 vs. MI/R
Fig. 6
Fig. 6
Mdivi-1 suppressed myocardial apoptosis following myocardial ischemia/reperfusion (MI/R) in diabetic mice. a Top representative terminal deoxynucleotidyl nick-end labeling (TUNEL)-stained and 4’,6-diamino-2-phenylindole (DAPI)-stained photomicrographs. Original magnification ×400. Bottom percentage of apoptotic cells (green fluorescence)/the total number of nucleated cells (blue fluorescence). b Myocardial caspase-3 activity (fold over Sham). MI/R group means diabetic mice subjected to MI/R and vehicle (dimethyl sulfoxide) administration. Values are mean ± SEM. N = 8 hearts for each group. **P < 0.01 vs. Sham. ## P < 0.01 vs. MI/R
Fig. 7
Fig. 7
Mdivi-1 suppressed oxidative stress following myocardial ischemia/reperfusion (MI/R) in diabetic mice. a The contents of myocardial malondialdehyde (MDA). b The activity of mitochondrial manganese superoxide dismutase (MnSOD). MI/R group means diabetic mice subjected to MI/R and vehicle (dimethyl sulfoxide) administration. Values are mean ± SEM. N = 8 hearts for each group. **P < 0.01 vs. Sham. # P < 0.05, ## P < 0.01 vs. MI/R

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