Imine stilbene analog ameliorate isoproterenol-induced cardiac hypertrophy and hydrogen peroxide-induced apoptosis
Imine stilbene analog ameliorate isoproterenol-induced cardiac hypertrophy and hydrogen peroxide-induced apoptosis
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DOI：
10.1016/j.freeradbiomed.2020.04.014
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发表时间：
2020-06-01
影响因子：
7.4
通讯作者：
Bhadra, Manika Pal
中科院分区：
文献类型：
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作者：
Raut, Ganesh Kumar;Manchineela, Sairam;Bhadra, Manika Pal
心脏肥大是机体对应激的一种适应性反应，目的是维持正常的心脏功能。然而，持续的压力导致病理性肥大，伴随着适应不良反应，最终导致心力衰竭。结论：1.在细胞水平上，心肌细胞肥大表现为心肌细胞体积增大、胎儿基因标志物重新激活、肌节解体和转录重构，这些变化受心脏特异性转录因子MEF2、GATA 4和即刻早期基因c-jun、c-fos等的调控。已经探索并确定肥大过程与氧化应激相关，并由涉及几种终末应激激酶如P38、JNK和ERK 1/2的途径介导。芪类化合物是具有生物活性的多酚，早期的研究表明亚胺芪通过作为Sirt1的调节剂发挥心脏保护和抗衰老作用。本研究旨在设计合成一系列二苯乙烯亚胺类化合物，探讨其抗心肌肥厚作用及其对心肌肥厚和凋亡的调控机制。有趣的是，类似物之一，化合物3e（10 μ M）通过显示肌细胞大小的显著减小而减轻异丙肾上腺素（ISO，25 μ M）诱导的大鼠心肌细胞（H9c2）细胞肥大。此外，化合物3e还通过激活代谢应激传感器AMPK来恢复心脏功能。此外，分子对接研究显示化合物3e和GSK 3 β之间的稳定结合，表明化合物3e可以直接调节GSK 3 β活性并改善ISO诱导的心脏肥大。与此一致，化合物3e还通过将表达降低至接近对照条件来调节所有肥大诱导终末激酶的串扰。该化合物还减轻了H2O2（100 μ M）介导的ROS和正常化的异常线粒体需氧量在肥大的条件下，表明该化合物的可能性，以显示承诺在心脏肥大中发挥作用。
Cardiac hypertrophy is an adaptive response to stress, in order to maintain proper cardiac function. However, sustained stress leads to pathological hypertrophy accompanied by maladaptive responses and ultimately heart failure. At the cellular level, cardiomyocyte hypertrophy is characterized by an increase in myocyte size, reactivation of the fetal gene markers, disassembly of the sarcomere and transcriptional remodelling which are regulated by heart-specific transcription factors like MEF2, GATA4 and immediate early genes like c-jun and c-fos.2. It has been explored and established that the hypertrophic process is associated by oxidative stress and mediated by pathways involving several terminal stress kinases like P38, JNK and ERK1/2. Stilbenoids are bioactive polyphenols and earlier studies have shown that imine stilbene exert cardioprotective and anti aging effects by acting as modulators of Sirt1. The present study was aimed at designing and synthesizing a series of imine stilbene analogs and investigate its anti hypertrophic effects and regulatory mechanism in cardiac hypertrophy and apoptosis. Interestingly one of the analog, compound 3e (10 mu M) alleviated isoproterenol (ISO, 25 mu M) induced hypertrophy in rat cardiomyocyte (H9c2) cells by showing a marked decrease in the myocyte size. Further, compound 3e also restored the cardiac function by activating the metabolic stress sensor, AMPK. Moreover, molecular docking studies showed stable binding between compound 3e and GSK3 beta suggesting that compound 3e may directly regulate GSK3 beta activity and ameliorate ISO-induced cardiac hypertrophy. In agreement with this, compound 3e also modulated the crosstalk of all the hypertrophy inducing terminal Kinases by bringing down the expression to near control conditions. The compound also relieved H2O2 (100 mu M) mediated ROS and normalized abnormal mitochondrial oxygen demand in hypertrophic conditions indicating the possibility of the compound to show promise in playing a role in cardiac hypertrophy.