阿霉素对心肌肌醇依赖酶I-JNK通路的影响

目的探讨肌醇依赖酶1（IRE1）-JNK通路是否参与阿霉素致心力衰竭（HF）效应的作用。方法阿霉素（adriamycin，Adr）致HF大鼠作为Adr组（n=15），同龄健康大鼠作为对照组（n=10）；将乳鼠心肌细胞随机分为对照组和Adr组（1umol／L）。心脏超声后，流式细胞仪和蛋白印迹等分别检测细胞凋亡率（AR）、IRE1、X盒结合蛋白1（XBP1）、TNF受体相关因子2（TRAF2）、c—Jun凋亡信号调节激酶（ASKl）和JNK等的表达。结果1．Adr在体成功构建HF模型，而体外干预显著增加心肌细胞AR（P％0．001）；2．不管在体内抑或在体外，Adr组IRE1α和pIRE1α水平均显著高于相应对照组（P〈0．001）；3．与相应对照组相比，Adr组XBP1蛋白均显著上调（P〈0．001）；4．体内和体外Adr组TRAF2蛋白的表达显著高于相应对照组（P〈0．001）；5．Adr组ASK1、p-ASK1和磷酸化水平（即p-ASK1与总ASK1比值）显著高于相应对照组（P〈0．001）；6．不管在体内抑或在体外，Adr组JNK1／2、p-JNKl／2蛋白和其磷酸化水平（p-JNK1／2与总JNK1／2比值）均显著高于相应对照组（P〈0．001）。结论Adr通过肌醇依赖酶1（IRE1）-ASK—JNK内质网通路介导其致心肌毒性并进而促发HF。

Cardiotoxic effect of adriamycin on inositol-requiring enzyme-JNK pathway

Objective To elucidate whether adriamycin （Adr）-induced heart failure （HF） was mediated by the inositol-requiring enzyme 1 （IRE 1 ）- C-Jun N N-terminal kinase （JNK） pathway. Methods HF or cardiomyocyte insult, induced by Adr, was referred to as the Adr group, and the healthy age-matched rats or normal cardiomyocytes served as controls. Left ventricular ejection fraction （LVEF） was analyzed by echocardiography and apoptosis ratio （AR） was assayed by FCM. In addition, the protein expressions of IRE 1, X box-binding protein 1 （XBP 1）, TNF-receptor-associated factor 2 （TRAF 2）, apoptosis-signal-regulating kinase 1 （ASK1） and JNK1/2, were assayed by western bolt, respectively. Results 1. HF was performed and AR of cardiomyocytes was significantly up-regulated by Adr （P〈0. 001）, in vivo and ex vivo; 2. Both IRE1a and p-IRE1a were significantly up-regulated in Adr than in control groups （P〈0. 001）, in vivo and in vitro. 3. Adr markedly increased the expression of XBP1 protein （P〈0. 001）, in vivo and in vitro; 4. TRAF2 protein was significantly increased by Adr, compared with that of the control group （P〈0. 001）, in vivo and in vitro. 5. ASK1, p-ASK1 and its phosphorylation （normalized to total ASK-l） were markedly upregulated by Adr, in vivo and in vitro; 6. JNK1/2, p-JNK1/2 and its phosphorylation （normalized to total JNK1/2） were significantly higher in the Adr group than in the control group （P〈0. 001）, in vivo and in vitro. Conclusion The effect of Adr inducing HF is at least partly fulfilled through adjusting the IRE1- ASK-JNK pathway.