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首页> 外文期刊>FEBS Open Bio >Novel ASK1 inhibitor AGI‐1067 improves AGE‐induced cardiac dysfunction by inhibiting MKKs/p38 MAPK and NF‐κB apoptotic signaling
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Novel ASK1 inhibitor AGI‐1067 improves AGE‐induced cardiac dysfunction by inhibiting MKKs/p38 MAPK and NF‐κB apoptotic signaling

机译：新型ASK1抑制剂AGI-1067通过抑制MKKs / p38 MAPK和NF-κB凋亡信号转导改善AGE引起的心脏功能障碍

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Heart failure has been identified as one of the clinical manifestations of diabetic cardiovascular complications. Excessive myocardium apoptosis characterizes cardiac dysfunctions, which are correlated with an increased level of advanced glycation end products ( AGE s). In this study, we investigated the participation of reactive oxygen species ( ROS ) and the involvements of apoptosis signal‐regulating kinase 1 ( ASK 1)/mitogen‐activated protein kinase ( MAPK ) kinases ( MKK s)/p38 MAPK and nuclear factor κB ( NF ‐κB) pathways in AGE ‐induced apoptosis‐mediated cardiac dysfunctions. The antioxidant and therapeutic effects of a novel ASK 1 inhibitor, AGI ‐1067, were also studied. Myocardium and isolated primary myocytes were exposed to AGE s and treated with AGI ‐1067. Invasive hemodynamic and echocardiographic assessments were used to evaluate the cardiac functions. ROS formation was evaluated by dihydroethidium fluorescence staining. A terminal deoxynucleotidyl transferase dUTP nick end labelling assay was used to detect the apoptotic cells. ASK 1 and NADPH activities were determined by kinase assays. The association between ASK 1 and thioredoxin 1 (Trx1) was assessed by immunoprecipitation. Western blotting was used to evaluate the phosphorylation and expression levels of proteins. Our results showed that AGE exposure significantly activated ASK 1/ MKK s/p38 MAPK , which led to increased cardiac apoptosis and cardiac impairments. AGI ‐1067 administration inhibited the activation of MKK s/p38 MAPK by inhibiting the disassociation of ASK 1 and Trx1, which suppressed the AGE ‐induced myocyte apoptosis. Moreover, the NF ‐κB activation as well as the ROS generation was inhibited. As a result, cardiac functions were improved. Our findings suggested that AGI ‐1067 recovered AGE ‐induced cardiac dysfunction by blocking both ASK 1/ MKK s/p38 and NF ‐κB apoptotic signaling pathways.
机译：心力衰竭已被确定为糖尿病性心血管并发症的临床表现之一。过度的心肌细胞凋亡是心脏功能障碍的特征，其与晚期糖基化终末产物（AGE）水平的升高有关。在这项研究中，我们研究了活性氧（ROS）的参与以及凋亡信号调节激酶1（ASK 1）/促分裂原活化蛋白激酶（MAPK）激酶（MKK s）/ p38 MAPK和核因子κB的参与（NFκB）通路在AGE诱导的细胞凋亡介导的心脏功能障碍中发挥作用。还研究了新型ASK 1抑制剂AGI-1067的抗氧化和治疗作用。将心肌和分离的原代心肌细胞暴露于AGEs并用AGI-1067处理。使用有创血流动力学和超声心动图评估来评估心脏功能。通过二氢乙啶荧光染色评估ROS的形成。使用末端脱氧核苷酸转移酶dUTP缺口末端标记测定法检测凋亡细胞。通过激酶测定法确定ASK 1和NADPH活性。 ASK 1和硫氧还蛋白1（Trx1）之间的关联通过免疫沉淀进行评估。使用蛋白质印迹法评估蛋白质的磷酸化和表达水平。我们的结果表明，AGE暴露可显着激活ASK 1 / MKK s / p38 MAPK，从而导致心脏凋亡和心脏损害增加。 AGI-1067给药通过抑制ASK 1和Trx1的分离来抑制MKK s / p38 MAPK的激活，从而抑制了AGE诱导的心肌细胞凋亡。此外，NF-κB的活化以及ROS的生成都受到抑制。结果，心脏功能得到改善。我们的发现表明，AGI-1067通过阻断ASK 1 / MKK s / p38和NF-κB凋亡信号通路来恢复AGE引起的心脏功能障碍。

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