Wang Anxing, Zhang Huijun, Liang Zeming, Xu Kai, Qiu Weifeng, Tian Yongbo, Guo Hong, Jia Junzheng, Xing Erke, Chen Rufei, Xiang Zongxing, Liu Jia
The Second Department of Cardiovascular, Baoji City Traditional Chinese Medicine Hospital, Baoji, Shaanxi 721001, PR China.
The Second Department of Cardiovascular, Baoji City Traditional Chinese Medicine Hospital, Baoji, Shaanxi 721001, PR China.
Eur J Pharmacol. 2016 Oct 5;788:280-285. doi: 10.1016/j.ejphar.2016.06.038. Epub 2016 Jun 23.
Myocardial ischemia is one of the main causes of sudden cardiac death worldwide. Depending on the cell type and stimulus, ERK activity mediates different anti-proliferative events, such as apoptosis, autophagy, and senescence. The aim of this study was to determine the protective effect of 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126), an ERK kinase inhibitor, on myocardial ischemia/reperfusion (I/R) injury and the mechanisms involved. An I/R model was established in vivo in C57BL/6 mice and in vitro using mouse cardiomyocytes, respectively. To evaluate the protective effects of U0126 on I/R injury, we measured the myocardial infarct area, apoptosis, and autophagy. Our data indicated that pretreatment with U0126 significantly reduced the infarct area caused by I/R. Moreover, U0126 reduced the caspase-3 activity and the number of TUNEL-positive cardiomyocytes, which together indicate decreased apoptosis. Additionally, U0126 remarkable reduced the level of Beclin-1 and LC3 and increased p62 expression, which indicates that U0126 suppressed H/R-induced autophagy. Furthermore, the relationship between U0126 and MEK/ERK pathway activation in H/R-induced cardiomyocytes was also investigated. U0126 ameliorated H/R injury through inhibition of the MEK/ERK pathway and by suppressing in the downstream EGR-1 expression. Together, our research suggests that U0126 may protect against H/R injury by preventing H/R-induced myocardium apoptosis and autophagy via the MEK/ERK/EGR-1 pathway, and may be a potential therapeutic approach for attenuating myocardial I/R injury.
心肌缺血是全球范围内心源性猝死的主要原因之一。根据细胞类型和刺激因素，细胞外信号调节激酶（ERK）活性介导不同的抗增殖事件，如细胞凋亡、自噬和衰老。本研究的目的是确定ERK激酶抑制剂1,4 - 二氨基 - 2,3 - 二氰基 - 1,4 - 双[2 - 氨基苯硫基]丁二烯（U0126）对心肌缺血/再灌注（I/R）损伤的保护作用及其相关机制。分别在C57BL/6小鼠体内和体外使用小鼠心肌细胞建立了I/R模型。为了评估U0126对I/R损伤的保护作用，我们测量了心肌梗死面积、细胞凋亡和自噬情况。我们的数据表明，U0126预处理显著减小了I/R引起的梗死面积。此外，U0126降低了半胱天冬酶 - 3活性和TUNEL阳性心肌细胞数量，这共同表明细胞凋亡减少。另外，U0126显著降低了Beclin - 1和LC3水平并增加了p62表达，这表明U0126抑制了缺氧/复氧（H/R）诱导的自噬。此外，还研究了U0126与H/R诱导的心肌细胞中MEK/ERK通路激活之间的关系。U0126通过抑制MEK/ERK通路并抑制下游早期生长反应蛋白 - 1（EGR - 1）表达来改善H/R损伤。总之，我们的研究表明，U0126可能通过MEK/ERK/EGR - 1通路预防H/R诱导的心肌细胞凋亡和自噬，从而保护心肌免受H/R损伤，并且可能是减轻心肌I/R损伤的一种潜在治疗方法。
