Department of Anesthesiology, Shanxi Bethune Hospital, 99, Longcheng Street, 030032, Taiyuan, China.
BMC Cardiovasc Disord. 2021 Feb 16;21(1):96. doi: 10.1186/s12872-021-01906-w.
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.
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.
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.
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.
七氟醚后处理（SevP）可有效减轻心肌缺血/再灌注（I/R）损伤，但在糖尿病心肌中效果不佳。先前的研究表明，氧化应激增加在糖尿病组织中起着重要作用。值得注意的是，由 dynamin-related protein 1 (Drp1) 介导的线粒体裂变是活性氧产生的上游途径。SevP 在糖尿病心肌中无效是否与 Drp1 依赖性线粒体裂变有关尚不清楚。本研究旨在探讨 Drp1 在糖尿病心肌中的重要作用，并研究 Drp1 抑制是否可以恢复 SevP 的心脏保护作用。
在研究的第一部分，成年雄性 Sprague-Dawley 大鼠分为 6 组。糖尿病组大鼠给予高脂高糖饮食 8 周，腹腔注射链脲佐菌素（35mg/kg）。左前降支冠状动脉闭塞 30min 后再灌注 120min 诱导心肌 I/R。SevP 在再灌注前 1min 持续吸入 2.5%七氟醚 10min。在研究的第二部分，我们应用 mdivi-1 来研究 Drp1 抑制是否可以恢复 SevP 在糖尿病心肌中的心脏保护作用。检测心肌梗死面积、线粒体超微结构、凋亡指数、SOD 活性、MDA 含量和 Drp1 表达。
TTC 染色和 TUNEL 结果表明，糖尿病心肌梗死面积和凋亡指数增加。然而，SevP 显著减轻了正常心肌的 I/R 损伤，但对糖尿病心肌没有作用。此外，我们发现 Drp1 表达升高，同时伴有糖尿病心肌更严重的分裂诱导结构损伤和氧化应激。有趣的是，我们发现 mdivi-1 恢复了 SevP 的有益作用，显著抑制了线粒体裂变和氧化应激。
本研究表明，Drp1 依赖性线粒体裂变在糖尿病心肌 I/R 中起关键作用，并强烈表明 Drp1 抑制可能恢复 SevP 在糖尿病大鼠中的心脏保护作用。
