Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model.
Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model.
复制标题
DOI：
10.1097/ccm.0000000000000817
复制
发表时间：
2015-02
影响因子：
8.8
通讯作者：
Archer SL
中科院分区：
文献类型：
--
作者：
Sharp WW;Beiser DG;Fang YH;Han M;Piao L;Varughese J;Archer SL
尽管心肺复苏术（CPR）和低温治疗的应用取得了进展，但心脏骤停后的生存率很低。动力蛋白相关蛋白1（Dynamin related protein 1，Drp 1）是线粒体分裂的调节因子，是缺血/再灌注损伤后活性氧生成、心肌坏死和左心室功能的重要决定因素，但其在心脏骤停中的作用尚不清楚。我们假设，Drp 1抑制将改善存活率，心脏血流动力学，和线粒体功能在体内心脏骤停模型。实验室调查。大学实验室麻醉和通气的成年雌性C57 BL/6野生型小鼠经历8分钟KCl诱导的心脏骤停，随后进行90秒的CPR。然后将小鼠随机盲法单次静脉注射Mdivi-1（0.24 mg/kg）、小分子Drp 1抑制剂或溶媒（DMSO）。心脏骤停复苏后，线粒体分裂证明Drp 1易位到线粒体膜和线粒体大小的减少。线粒体分裂与乳酸增加和氧化损伤证据相关。Mdivi-1管理CPR期间抑制Drp 1激活，保存线粒体形态，并减少氧化损伤。Mdivi-1还减少了恢复自主循环的时间（ROSC）116±4对143±7秒（p<. 001)心肺复苏术后心肌功能增强。这些改善与生存率的显著增加（65% vs. 33%）和心脏骤停后72小时神经系统评分的改善相关。心脏骤停后抑制Drp 1可改善至ROSC的时间和心肌血流动力学，从而改善心脏骤停小鼠模型的存活率和神经学结局。线粒体分裂的药理学靶向可能是心脏骤停的一种有前途的治疗方法。
Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation (CPR) and the use of therapeutic hypothermia. Dynamin related protein 1 (Drp1), a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that Drp1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest. Laboratory investigation. University laboratory Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-min KCl induced cardiac arrest followed by 90 seconds of CPR. Mice were then blindly randomized to a single intravenous injection of Mdivi-1 (0.24 mg/kg), a small molecule Drp1 inhibitor or vehicle (DMSO). Following resuscitation from cardiac arrest, mitochondrial fission was evidenced by Drp1 translocation to the mitochondrial membrane and a decrease in mitochondrial size. Mitochondrial fission was associated with increased lactate and evidence of oxidative damage. Mdivi-1 administration during CPR inhibited Drp1 activation, preserved mitochondrial morphology, and decreased oxidative damage. Mdivi-1 also reduced the time to return of spontaneous circulation (ROSC) 116±4 vs. 143±7 sec (p<. 001) during CPR and enhanced myocardial performance post-ROSC. These improvements were associated with significant increases in survival (65% vs. 33%) and improved neurological scores up to 72 hours post cardiac arrest. Post cardiac arrest inhibition of Drp1 improves time to ROSC and myocardial hemodynamics resulting in improved survival and neurological outcomes in a murine model of cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest.