AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats.
AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats.
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DOI：
10.1016/j.redox.2018.09.022
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发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Mo J;Enkhjargal B;Travis ZD;Zhou K;Wu P;Zhang G;Zhu Q;Zhang T;Peng J;Xu W;Ocak U;Chen Y;Tang J;Zhang J;Zhang JH
氧化应激和神经元凋亡已被证明是蛛网膜下腔出血（SAH）后早期脑损伤（EBI）的关键特征。以前的研究表明Mas受体激活在脑中启动抗氧化和抗凋亡作用。然而，Mas激活是否可以减轻SAH后的氧化应激和神经元凋亡仍不清楚。为了研究Mas对SAH诱导的氧化应激损伤和神经元凋亡的有益作用，共196只大鼠进行了SAH的血管内穿孔模型。AVE 0991（AVE）是Mas的选择性激动剂，在SAH诱导后1h鼻内给药。分别于SAH诱导前1 h和48 h侧脑室注射选择性Mas抑制剂A779和UCP-2小干扰核糖核酸（siRNA）。进行神经学测试、免疫荧光、TUNEL、Fluoro-Jade C、DHE染色和Western印迹实验。我们发现，与SAH+赋形剂组相比，AVE激活Mas显著改善SAH+AVE组的神经行为评分，减少氧化应激和神经元凋亡。此外，AVE处理显著促进CREB磷酸化和UCP-2表达，上调Bcl-2表达，下调Romo-1和Bax表达。在SAH+AVE+A779组和SAH + AVE+UCP-2 siRNA组中，AVE的保护作用分别被i.c.v注射A779和UCP-2 siRNA逆转。总之，我们的数据提供了证据表明，AVE激活Mas通过Mas/PKA/p-CREB/UCP-2途径减少SAH后的氧化应激损伤和神经元凋亡。此外，我们的研究表明，Mas可能是一个新的治疗SAH的早期脑损伤的治疗靶点。蛛网膜下腔出血后RAS的Mas轴受到抑制。AVE 0991减少SAH诱导的神经元凋亡和变性。AVE 0991改善SAH后的神经功能障碍。AVE 0991的抗凋亡作用可能通过Mas/PKA/CREB/UCP-2途径介导。
Oxidative stress and neuronal apoptosis have been demonstrated to be key features in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have indicated that Mas receptor activation initiates an anti-oxidative and anti-apoptotic role in the brain. However, whether Mas activation can attenuate oxidative stress and neuronal apoptosis after SAH remains unknown. To investigate the beneficial effect of Mas on oxidative stress injury and neuronal apoptosis induced by SAH, a total of 196 rats were subjected to an endovascular perforation model of SAH. AVE 0991 (AVE), a selective agonist of Mas, was administered intranasally 1 h after SAH induction. A779, a selective inhibitor of Mas, and small interfering ribonucleic acid (siRNA) for UCP-2 were administered by intracerebroventricular (i.c.v) injection at 1 h and 48 h before SAH induction respectively. Neurological tests, immunofluorescence, TUNEL, Fluoro-Jade C, DHE staining, and Western blot experiments were performed. We found that Mas activation with AVE significantly improved neurobehavioral scores and reduced oxidative stress and neuronal apoptosis in SAH+AVE group compared with SAH+vehicle group. Moreover, AVE treatment significantly promoted phosphorylation of CREB and the expression UCP-2, as well as upregulated expression of Bcl-2 and downregulation of Romo-1 and Bax. The protective effects of AVE were reversed by i.c.v injection of A779 and UCP-2 siRNA in SAH+AVE+A779 and SAH+AVE+UCP-2 siRNA groups, respectively. In conclusion, our data provides evidence that Mas activation with AVE reduces oxidative stress injury and neuronal apoptosis through Mas/PKA/p-CREB/UCP-2 pathway after SAH. Furthermore, our study indicates that Mas may be a novel therapeutic treatment target in early brain injury of SAH. Mas axis of brain RAS was suppressed after SAH. AVE 0991 reduces neuronal apoptosis and degeneration induced by SAH. AVE 0991 improves neurological impairments after SAH. The anti-apoptotic effect of AVE 0991 was mediated through Mas/PKA/CREB/UCP-2 pathway.
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影响因子：
3.9
作者：
Lara, Lucienne S.;Vives, Diogo;Caruso-Neves, Celso
通讯作者：
Caruso-Neves, Celso
影响因子：
4.2
作者：
Figueroa, S;Oset-Gasque, MJ;González, MP
通讯作者：
González, MP
影响因子：
6.3
作者：
Enkhjargal, Budbazar;McBride, Devin W.;Zhang, John H.
通讯作者：
Zhang, John H.
影响因子：
11.4
作者：
Cobley JN;Fiorello ML;Bailey DM
通讯作者：
Bailey DM
DOI：
10.1161/hypertensionaha.115.05185
发表时间：
2015-07
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Bennion DM;Haltigan EA;Irwin AJ;Donnangelo LL;Regenhardt RW;Pioquinto DJ;Purich DL;Sumners C
通讯作者：
Sumners C