Acute ethanol exposure-induced autophagy-mediated cardiac injury via activation of the ROS-JNK-Bcl-2 pathway
Acute ethanol exposure-induced autophagy-mediated cardiac injury via activation of the ROS-JNK-Bcl-2 pathway
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通过激活 ROS-JNK-Bcl-2 途径，急性乙醇暴露诱导自噬介导的心脏损伤
DOI：
10.1002/jcp.25934
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发表时间：
2018
影响因子：
5.6
通讯作者：
Jin Litai
中科院分区：
文献类型：
--
作者：
Zhu Zhongxin;Huang Yewei;Lv Lingchun;Tao Youli;Shao Minglong;Zhao Congcong;Xue Mei;Sun Jia;Niu Chao;Wang Yang;Kim Sunam;Cong Weitao;Mao Wei;Jin Litai
酗酒与心脏自噬增加有关，并经常引发心脏损伤。鉴于自噬在各种心脏疾病中的重要作用，本研究旨在研究自噬在乙醇诱导的心脏损伤中的作用及其机制。我们的研究表明，在体内和体外，乙醇暴露增加了LC 3-II和LC 3-II阳性斑点的水平，并促进了心肌细胞凋亡。此外，我们发现乙醇诱导自噬和心脏损伤主要是通过连续触发活性氧（ROS）积累，c-Jun NH 2-末端激酶（JNK）激活，Bcl-2磷酸化和Beclin 1/Bcl-2复合物解离。相比之下，在小鼠心脏和培养细胞中用药理学试剂抑制乙醇诱导的自噬通量显著减轻了乙醇诱导的心肌细胞凋亡和心脏损伤。用抗氧化剂N-乙酰半胱氨酸（NAC）消除ROS或用JNK抑制剂SP 600125抑制JNK可减少乙醇诱导的自噬和随后的自噬介导的凋亡。此外，金属硫蛋白（MT），它可以减少活性氧和氮物种，也减弱乙醇诱导的自噬和细胞凋亡的MT-TG小鼠。总之，我们的研究结果表明，急性乙醇暴露主要通过ROS-JNK-Bcl-2信号通路诱导自噬介导的心脏毒性和损伤。
Binge drinking is associated with increased cardiac autophagy, and often triggers heart injury. Given the essential role of autophagy in various cardiac diseases, this study was designed to investigate the role of autophagy in ethanol‐induced cardiac injury and the underlying mechanism. Our study showed that ethanol exposure enhanced the levels of LC3‐II and LC3‐II positive puncta and promoted cardiomyocyte apoptosis in vivo and in vitro. In addition, we found that ethanol induced autophagy and cardiac injury largely via the sequential triggering of reactive oxygen species (ROS) accumulation, activation of c‐Jun NH2‐terminal kinase (JNK), phosphorylation of Bcl‐2, and dissociation of the Beclin 1/Bcl‐2 complex. By contrast, inhibition of ethanol‐induced autophagic flux with pharmacologic agents in the hearts of mice and cultured cells significantly alleviated ethanol‐induced cardiomyocyte apoptosis and heart injury. Elimination of ROS with the antioxidant N‐acetyl cysteine (NAC) or inhibition of JNK with the JNK inhibitor SP600125 reduced ethanol‐induced autophagy and subsequent autophagy‐mediated apoptosis. Moreover, metallothionein (MT), which can scavenge reactive oxygen and nitrogen species, also attenuated ethanol‐induced autophagy and cell apoptosis in MT‐TG mice. In conclusion, our findings suggest that acute ethanol exposure induced autophagy‐mediated heart toxicity and injury mainly through the ROS‐JNK‐Bcl‐2 signaling pathway.