Inhibition of dynamin-related protein 1 protects against myocardial ischemia-reperfusion injury in diabetic mice.
Inhibition of dynamin-related protein 1 protects against myocardial ischemia-reperfusion injury in diabetic mice.
复制标题
抑制动力相关蛋白 1 可预防糖尿病小鼠心肌缺血再灌注损伤
DOI：
10.1186/s12933-017-0501-2
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发表时间：
2017-02-07
影响因子：
9.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Ding M;Dong Q;Liu Z;Liu Z;Qu Y;Li X;Huo C;Jia X;Fu F;Wang X
许多心脏保护药物对心肌缺血/再灌注（MI/R）的糖尿病心脏不能发挥其保护作用。确定糖尿病与MI/R损伤的分子基础具有重要的科学意义，并可能提供有效的治疗方法。动力蛋白相关蛋白1（Drp 1）介导的线粒体分裂在非糖尿病条件下的MI/R损伤中起重要作用。重要的是，最近的研究表明，Drp 1介导的线粒体分裂在糖尿病小鼠的心肌中增强。以上结果提示，Drp 1可能是糖尿病与心肌梗死/再灌注损伤联系的重要分子之一。我们假设抑制Drp 1可能有效减少糖尿病心脏的MI/R损伤。高脂饮食和链脲佐菌素诱导的糖尿病小鼠进行MI/R或假手术。在再灌注开始前15 min给予Drp 1小分子抑制剂Mdivi-1（1.2 mg/kg）或溶媒。结果指标包括线粒体形态、线粒体功能、心肌损伤、心功能和氧化应激。线粒体分裂显着增加MI/R后，证明了增强易位的Drp 1的线粒体和线粒体的大小减少。将Mdivi-1递送到糖尿病小鼠中显著抑制了MI/R后Drp 1向线粒体的移位并减少了线粒体分裂。在糖尿病心脏中抑制Drp 1可改善MI/R后的线粒体功能和心脏功能。此外，抑制Drp 1可减少心肌梗死面积和血清心肌肌钙蛋白I和乳酸脱氢酶活性。这些心脏保护作用与减少心肌细胞凋亡和丙二醛的产生和增加抗氧化酶锰超氧化物歧化酶的活性有关。药物抑制Drp 1可防止糖尿病小鼠线粒体分裂并减少MI/R损伤。这些发现表明Drp 1可能是糖尿病心脏并发症的潜在新治疗靶点。
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. 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. 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. 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.