首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion.
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The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion.

机译:局灶性脑缺血/再灌注后,丝氨酸蛋白酶Omi / HtrA2参与XIAP裂解和神经元细胞死亡。

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摘要

Omi/HtrA2 is a pro-apoptotic mitochondrial serine protease involved in both forms of apoptosis, caspase-dependent as well as caspase-independent cell death. However, the impact of Omi/HtrA2 in the apoptotic cell machinery that takes place in vivo under pathological conditions such as cerebral ischemia remains unknown. The present study was monitored in order to examine whether Omi/HtrA2 plays a decisive role in apoptosis observed after focal cerebral ischemia in rats. Male adult rats were subjected to 90min of focal cerebral ischemia followed by reperfusion and treated with vehicle or ucf-101, a novel and specific Omi/HtrA2 inhibitor, prior reperfusion. Focal cerebral ischemia/reperfusion induced a mitochondrial up-regulation of Omi/HtrA2 and significantly increased cytosolic accumulation of Omi/HtrA2. Furthermore, ischemia led to activation of caspase-3 and degradation X-linked inhibitor of apoptosis protein (XIAP). Treatment of animals prior ischemia with ucf-101, the specific inhibitor of Omi/HtrA2,was able to (1) reduce the number of TUNEL-positive cells, to (2) attenuate the XIAP-breakdown and to (3) reduce the infarct size. This study shows for the first time that focal cerebral ischemia in rats results in Omi/HtrA2 translocation from the mitochondria to the cytosol, where it participates in neuronal cell death. Blocking the proteolytic activity of Omi/HtrA2 with specific inhibitors, such as the ucf-101, could be a novel way to afford neuroprotection and minimize cellular damage in cerebral ischemia/reperfusion.
机译:Omi / HtrA2是一种促凋亡的线粒体丝氨酸蛋白酶,参与凋亡的两种形式,即caspase依赖性和caspase依赖性细胞死亡。但是,Omi / HtrA2对在病理条件下(例如脑缺血)在体内发生的凋亡细胞机制的影响仍然未知。监测本研究以检查Omi / HtrA2是否在大鼠局灶性脑缺血后观察到的凋亡中起决定性作用。对雄性成年大鼠进行90分钟的局灶性脑缺血,然后再灌注,并在再灌注之前用溶媒或ucf-101(一种新型的特异性Omi / HtrA2抑制剂)进行治疗。局灶性脑缺血/再灌注诱导Omi / HtrA2的线粒体上调并显着增加Omi / HtrA2的胞质积累。此外,局部缺血导致caspase-3的活化和X连锁的凋亡抑制蛋白(XIAP)的降解。使用Omi / HtrA2的特异性抑制剂ucf-101治疗缺血前的动物,能够(1)减少TUNEL阳性细胞的数量,至(2)减弱XIAP的分解,并至(3)减少梗塞尺寸。这项研究首次表明大鼠局灶性脑缺血导致Omi / HtrA2从线粒体转运到胞质溶胶,并参与神经元细胞死亡。用特定的抑制剂(例如ucf-101)阻断Omi / HtrA2的蛋白水解活性可能是一种提供神经保护作用并使脑缺血/再灌注中的细胞损伤最小化的新方法。

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