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Exogenous ubiquitin attenuates hypoxia/reoxygenation-induced cardiac myocyte apoptosis via the involvement of CXCR4 and modulation of mitochondrial homeostasis.
Biochemistry and Cell Biology ( IF 2.4 ) Pub Date : 2020-01-22 , DOI: 10.1139/bcb-2019-0339
Suman Dalal 1, 2 , Christopher R Daniels 1 , Ying Li 1 , Gary L Wright 1 , Mahipal Singh 1 , Krishna Singh 1, 2, 3
Affiliation  

Exogenous ubiquitin (UB) plays a protective role in β-adrenergic receptor-stimulated and ischemia/reperfusion (I/R)-induced myocardial remodeling. Here, we report that UB treatment inhibits hypoxia/reoxygenation (H/R)-induced apoptosis in adult rat ventricular myocytes (ARVMs). The activation of Akt was elevated, whereas the activation of glycogen synthase kinase-3β was reduced in UB-treated cells post-H/R. The level of oxidative stress was lower, whereas the number of ARVMs with polarized mitochondria was significantly greater in the UB-treated samples. ARVMs express CXCR4 with majority of CXCR4 localized in the membrane fraction. CXCR4 antagonism using AMD3100, and siRNA-mediated knockdown of CXCR4 negated the protective effects of UB. Two mutated UB proteins (unable to bind CXCR4) had no effect on H/R-induced apoptosis, activation of Akt and GSK-3β, or oxidative stress. UB treatment enhanced mitochondrial biogenesis, and inhibition of mitochondrial fission using mdivi1 inhibited H/R-induced apoptosis. Ex vivo, UB treatment significantly decreased infarct size and improved functional recovery of the heart following global I/R. Activation of caspase-9, a key player of the mitochondrial death pathway, was significantly lower in UB-treated hearts post-I/R. UB, most likely acting via CXCR4, plays a protective role in H/R-induced myocyte apoptosis and myocardial I/R injury via modulation of mitochondrial homeostasis and the mitochondrial death pathway of apoptosis.

中文翻译:

外源性泛素通过 CXCR4 的参与和线粒体稳态的调节减弱缺氧/复氧诱导的心肌细胞凋亡。

外源性泛素 (UB) 在 β-肾上腺素能受体刺激和缺血/再灌注 (I/R) 诱导的心肌重塑中起保护作用。在这里,我们报告说 UB 治疗抑制了成年大鼠心室肌细胞 (ARVM) 中缺氧/复氧 (H/R) 诱导的细胞凋亡。在 H/R 后 UB 处理的细胞中,Akt 的活化升高,而糖原合酶激酶-3β 的活化降低。氧化应激水平较低,而在 UB 处理的样品中,具有极化线粒体的 ARVM 的数量显着增加。ARVM 表达 CXCR4,其中大部分 CXCR4 位于膜部分。使用 AMD3100 的 CXCR4 拮抗作用和 siRNA 介导的 CXCR4 敲低抵消了 UB 的保护作用。两种突变的 UB 蛋白(无法结合 CXCR4)对 H/R 诱导的细胞凋亡没有影响,Akt 和 GSK-3β 的激活,或氧化应激。UB 处理增强了线粒体生物发生,使用 mdivi1 抑制线粒体裂变可抑制 H/R 诱导的细胞凋亡。在体外,UB 治疗显着减少了梗塞面积并改善了整体 I/R 后心脏的功能恢复。在 I/R 后接受 UB 治疗的心脏中,caspase-9(线粒体死亡途径的关键参与者)的激活显着降低。UB 最有可能通过 CXCR4 起作用,通过调节线粒体稳态和细胞凋亡的线粒体死亡途径,在 H/R 诱导的心肌细胞凋亡和心肌 I/R 损伤中发挥保护作用。UB 治疗显着减少了梗塞面积并改善了整体 I/R 后心脏的功能恢复。在 I/R 后接受 UB 治疗的心脏中,caspase-9(线粒体死亡途径的关键参与者)的激活显着降低。UB 最有可能通过 CXCR4 起作用,通过调节线粒体稳态和细胞凋亡的线粒体死亡途径,在 H/R 诱导的心肌细胞凋亡和心肌 I/R 损伤中发挥保护作用。UB 治疗显着减少了梗塞面积并改善了整体 I/R 后心脏的功能恢复。在 I/R 后接受 UB 治疗的心脏中,caspase-9(线粒体死亡途径的关键参与者)的激活显着降低。UB 最有可能通过 CXCR4 起作用,通过调节线粒体稳态和细胞凋亡的线粒体死亡途径,在 H/R 诱导的心肌细胞凋亡和心肌 I/R 损伤中发挥保护作用。
更新日期:2020-01-22
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