Ye Xing, Lin Junyi, Lin Zebin, Xue Aimin, Li Liliang, Zhao Ziqin, Liu Li, Shen Yiwen, Cong Bin
Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, PR China.
The 8th Brigade of General Division of Criminal Investigation, Beijing Municipal Public Security Bureau, Beijing 100192, PR China.
Exp Cell Res. 2017 Oct 15;359(2):441-448. doi: 10.1016/j.yexcr.2017.08.027. Epub 2017 Aug 20.
Stress-induced cardiomyocyte apoptosis contributes to the pathogenesis of a variety of cardiovascular diseases, but how stress induces cardiomyocyte apoptosis remains largely unclear. The present study aims to investigate the effects of Axin1 up-regulated 1 (Axud1), a novel pro-apoptotic protein, on the cardiomyocyte survival and the underlying mechanisms. To this end, a rat model under restraint stress (RS) was established and in vitro stress-induced cardiomyocytes culture was achieved. Our data showed that Axud1 was upregulated in the rat myocardia after exposure to RS. Anti-apoptotic Bcl-2 was decreased, whereas pro-apoptotic Bax and Cleaved caspase-3 (Cc3) were increased in a time-dependent manner. The Wnt/β-catenin signaling was observed to be interestingly activated in heart undergoing RS. In addition, the treatment of norepinephrine (NE) to in vitro cardiomyocytes increased Axud1 level and induced cell apoptosis. Wnt/β-catenin signaling was consistently activated. Knockdown of Axud1 using specific siRNA blunted NE-induced cardiomyocytes apoptosis and also inactivated the Wnt/β-catenin signaling. XAV-939, an inhibitor of Wnt/β-catenin signaling, partially reversed the pro-apoptotic effect of NE. In conclusion, Axud1 accelerated stress-induced cardiomyocytes apoptosis through activation of Wnt/β-catenin signaling pathway. Our data provided novel evidence that therapeutic strategies against Axud1 or Wnt/β-catenin signaling might be promising in relation to RS-induced myocardial injury.
应激诱导的心肌细胞凋亡参与多种心血管疾病的发病机制，但应激如何诱导心肌细胞凋亡在很大程度上仍不清楚。本研究旨在探讨一种新型促凋亡蛋白Axin1上调蛋白1（Axud1）对心肌细胞存活的影响及其潜在机制。为此，建立了束缚应激（RS）大鼠模型，并实现了体外应激诱导的心肌细胞培养。我们的数据显示，暴露于RS后大鼠心肌中Axud1上调。抗凋亡蛋白Bcl-2减少，而促凋亡蛋白Bax和裂解的半胱天冬酶-3（Cc3）呈时间依赖性增加。有趣的是，在经历RS的心脏中观察到Wnt/β-连环蛋白信号被激活。此外，用去甲肾上腺素（NE）处理体外培养的心肌细胞可增加Axud1水平并诱导细胞凋亡。Wnt/β-连环蛋白信号持续被激活。使用特异性siRNA敲低Axud1可减弱NE诱导的心肌细胞凋亡，并使Wnt/β-连环蛋白信号失活。Wnt/β-连环蛋白信号抑制剂XAV-939部分逆转了NE的促凋亡作用。总之，Axud1通过激活Wnt/β-连环蛋白信号通路加速应激诱导的心肌细胞凋亡。我们的数据提供了新的证据，表明针对Axud1或Wnt/β-连环蛋白信号的治疗策略可能对RS诱导的心肌损伤具有前景。
