RTN1-C mediates cerebral ischemia/reperfusion injury via ER stress and mitochondria-associated apoptosis pathways.
RTN1-C mediates cerebral ischemia/reperfusion injury via ER stress and mitochondria-associated apoptosis pathways.
复制标题
RTN1-C通过内质网应激和线粒体相关凋亡途径介导脑缺血/再灌注损伤
DOI：
10.1038/cddis.2017.465
复制
发表时间：
2017-10-05
影响因子：
9
通讯作者：
Du J
中科院分区：
文献类型：
--
作者：
Gong L;Tang Y;An R;Lin M;Chen L;Du J
已发现reticulon家族诱导细胞凋亡、抑制轴突再生和调节蛋白质运输。然而，很少有人知道如何reticulon蛋白参与缺血过程中的神经元死亡促进过程的机制。在这里，我们报告，网状蛋白1-C（RTN 1-C）的表达与脑缺血/再灌注（I/R）损伤的进展。采用大鼠大脑中动脉闭塞（MCAO）脑卒中和氧糖剥夺再给氧（OGD/R）模型，我们确定RTN 1-C的表达在脑缺血/再灌注期间显著增加。RTN 1-C过表达诱导细胞凋亡，增加细胞对缺血损伤的脆弱性，而RTN 1-C敲低逆转缺血诱导的细胞凋亡，减弱OGD/R处理的神经细胞的脆弱性。从机制上讲，我们证明RTN 1-C介导的OGD/R诱导的细胞凋亡，通过ER应激和细胞凋亡相关的途径。RTN 1-C与Bcl-xL相互作用并增加其在ER中的定位，从而降低Bcl-xL的抗凋亡活性。最重要的是，Rtn 1-c的表达在体内敲减MCAO大鼠的细胞凋亡和减少I/R诱导的脑损伤的程度，评估梗死体积和神经评分。总的来说，这些数据首次支持RTN 1-C可能代表抗脑缺血/再灌注损伤疗法的新候选药物。
The reticulon family has been found to induce apoptosis, inhibit axon regeneration and regulate protein trafficking. However, little is known about the mechanisms of how reticulon proteins are involved in neuronal death-promoting processes during ischemia. Here, we report that the expression of Reticulon Protein 1-C (RTN1-C) was associated with the progression of cerebral ischemia/reperfusion (I/R) injury. Using a combination of rat middle cerebral artery occlusion (MCAO) stroke and oxygen-glucose deprivation followed by reoxygenation (OGD/R) models, we determined that the expression of RTN1-C was significantly increased during cerebral ischemic/reperfusion. RTN1-C overexpression induced apoptosis and increased the cell vulnerability to ischemic injury, whereas RTN1-C knockdown reversed ischemia-induced apoptosis and attenuated the vulnerability of OGD/R-treated neural cells. Mechanistically, we demonstrated that RTN1-C mediated OGD/R-induced apoptosis through ER stress and mitochondria-associated pathways. RTN1-C interacted with Bcl-xL and increased its localization in the ER, thus reducing the anti-apoptotic activity of Bcl-xL. Most importantly, knockdown of Rtn1-c expression in vivo attenuated apoptosis in MCAO rats and reduced the extent of I/R-induced brain injury, as assessed by infarct volume and neurological score. Collectively, these data support for the first time that RTN1-C may represent a novel candidate for therapies against cerebral ischemia/reperfusion injury.
登录
查看更多内容
DOI：
10.1038/jcbfm.2008.88
发表时间：
2009-01
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.1
作者：
Cuartero MI;de la Parra J;García-Culebras A;Ballesteros I;Lizasoain I;Moro MÁ
通讯作者：
Moro MÁ
影响因子：
4.8
作者：
Li, JZ;Lee, B;Lee, AS
通讯作者：
Lee, AS
影响因子：
8.3
作者：
BEDERSON, JB;PITTS, LH;BARTKOWSKI, H
通讯作者：
BARTKOWSKI, H
DOI：
10.1073/pnas.96.10.5752
发表时间：
1999-05-11
影响因子：
11.1
作者：
Krajewski, S;Krajewska, M;Reed, JC
通讯作者：
Reed, JC