PARK2-dependent mitophagy induced by acidic postconditioning protects against focal cerebral ischemia and extends the reperfusion window.
PARK2-dependent mitophagy induced by acidic postconditioning protects against focal cerebral ischemia and extends the reperfusion window.
复制标题
酸性后处理诱导的 PARK2 依赖性线粒体自噬可防止局灶性脑缺血并延长再灌注窗口
DOI：
10.1080/15548627.2016.1274596
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发表时间：
2017-03-04
期刊：
影响因子：
13.3
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Shen Z;Zheng Y;Wu J;Chen Y;Wu X;Zhou Y;Yuan Y;Lu S;Jiang L;Qin Z;Chen Z;Hu W;Zhang X
脑缺血后及时再灌注对于神经元存活至关重要。任何延长有限再灌注窗口的策略都将非常重要。酸性后处理（APC）是一种轻度酸中毒治疗方法，涉及在缺血后再灌注期间吸入二氧化碳。 APC 可减轻缺血性脑损伤，但其潜在机制尚未阐明。在这里，我们报告APC增强了皮质中动脉闭塞（MCAO）治疗的小鼠以及氧糖剥夺（OGD）治疗的脑切片和神经元中缺血再灌注诱导的线粒体自噬。抑制线粒体自噬会损害 APC 赋予的神经保护作用。此外，Park2 敲除小鼠中线粒体自噬和神经保护被消除，表明 PARK2 募集至线粒体促进了 APC 诱导的线粒体自噬。重要的是，在 MCAO 小鼠中，APC 治疗将有效再灌注窗口从 2 小时延长至 4 小时，并且通过外源表达 PARK2，该窗口进一步延长至 6 小时。综上所述，我们发现 PARK2 依赖性 APC 诱导的线粒体自噬使大脑对缺血性损伤具有抵抗力。 APC 治疗可能是延长中风治疗溶栓时间窗的有利策略。
Prompt reperfusion after cerebral ischemia is critical for neuronal survival. Any strategies that extend the limited reperfusion window will be of great importance. Acidic postconditioning (APC) is a mild acidosis treatment that involves inhaling CO2 during reperfusion following ischemia. APC attenuates ischemic brain injury although the underlying mechanisms have not been elucidated. Here we report that APC reinforces ischemia-reperfusion-induced mitophagy in middle cortical artery occlusion (MCAO)-treated mice, and in oxygen-glucose deprivation (OGD)-treated brain slices and neurons. Inhibition of mitophagy compromises neuroprotection conferred by APC. Furthermore, mitophagy and neuroprotection are abolished in Park2 knockout mice, indicating that APC-induced mitophagy is facilitated by the recruitment of PARK2 to mitochondria. Importantly, in MCAO mice, APC treatment extended the effective reperfusion window from 2 to 4 h, and this window was further extended to 6 h by exogenously expressing PARK2. Taken together, we found that PARK2-dependent APC-induced mitophagy renders the brain resistant to ischemic injury. APC treatment could be a favorable strategy to extend the thrombolytic time window for stroke therapy.