FoxO4 promotes myocardial ischemia-reperfusion injury: the role of oxidative stress-induced apoptosis.
FoxO4 promotes myocardial ischemia-reperfusion injury: the role of oxidative stress-induced apoptosis.
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FoxO4 促进心肌缺血再灌注损伤：氧化应激诱导细胞凋亡的作用。
DOI：
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发表时间：
2018
影响因子：
2.2
通讯作者：
Cheng Xiaoshu
中科院分区：
文献类型：
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作者：
Yu Lingling;Zhang Weifang;Huang Chahua;Liang Qian;Bao Huihui;Gong Zhijian;Xu Minxuan;Wang Zhenzhen;Wen Minhua;Cheng Xiaoshu
心肌细胞凋亡是缺血再灌注损伤的主要病理生理过程。FoxO 4最初被鉴定为限制细胞增殖并诱导细胞凋亡的肿瘤抑制因子，在心血管疾病中起着多种作用。然而，其对心肌I/R损伤的作用尚不清楚。本研究旨在探讨FoxO 4在心肌I/R损伤中的作用及其机制。对大鼠进行冠状动脉左前降支分支结扎/恢复，缺血30分钟，然后再灌注4小时。然后，进行氯化三苯基四氮唑（TTC）染色以评估梗死面积。经胸超声心动图评价心功能。末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）染色进行评估心肌细胞死亡。实时荧光定量PCR检测FoxO 4 mRNA的表达。进行蛋白质印迹以评估FoxO 4和切割的半胱天冬酶3蛋白的表达水平。进行免疫荧光染色以测量切割的半胱天冬酶3表达水平。分别采用羟胺法和TBA法测定丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性。进行二氢乙锭（DHE）染色以测量活性氧（ROS）的产生。我们成功地建立了大鼠心肌I/R损伤模型，并观察到心肌中FoxO 4表达增加。FoxO 4基因敲低显著保护大鼠免受心肌I/R损伤，如梗死面积显著减少和心功能改善所示。从机制上讲，I/R诱导大鼠心脏过度氧化应激，最有可能是由于FoxO 4水平增加，这些影响有助于诱导细胞凋亡。总之，FoxO 4/ROS通路代表了心肌I/R损伤过程中细胞凋亡的潜在新机制。靶向FoxO 4的治疗策略可能代表心肌I/R损伤的新治疗方法。
Myocardial cell apoptosis is the main pathophysiological process underlying ischemia-reperfusion (I/R) injury. FoxO4, which was initially identified as a tumor suppressor that limits cell proliferation and induces apoptosis, plays diverse roles in cardiovascular diseases. However, its contribution to myocardial I/R injury remains unclear. The present study was undertaken to explore the role of FoxO4 in apoptosis during myocardial I/R injury and its underlying mechanisms in vivo. Rats were subjected to ligation/restoration of the left anterior descending branch of the coronary artery and 30 min of ischemia, followed by 4 h of reperfusion. Then, triphenyltetrazolium chloride (TTC) staining was performed to evaluate the infarct size. Transthoracic echocardiography was performed to evaluate cardiac function. Terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) staining was performed to assess cell death in the myocardium. Real-time PCR was performed to measure FoxO4 mRNA expression. Western blots were performed to assess expression levels of the FoxO4 and cleaved caspase 3 proteins. Immunofluorescence staining was performed to measure cleaved caspase 3 expression levels. The hydroxylamine and TBA methods were performed to evaluate malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, respectively. Dihydroethidium (DHE) staining was performed to measure reactive oxygen species (ROS) generation. We successfully established a rat model of myocardial I/R injury and observed an increase in FoxO4 expression in the myocardium. FoxO4 knockdown significantly protected rats from myocardial I/R injury, as indicated by a marked decrease in infarct sizes and improvements in cardiac function. Mechanistically, I/R induced excessive oxidative stress in rat hearts, most likely as a result of increased FoxO4 levels, and these effects contributed to inducing apoptosis. In conclusion, the FoxO4/ROS pathway represents a potentially novel mechanism underlying apoptosis during myocardial I/R injury. Therapeutic strategies targeting FoxO4 might represent new treatments for myocardial I/R injury.