Dural effects of oxidative stress on cardiomyogenesis via Gata4 transcription and protein ubiquitination.
Dural effects of oxidative stress on cardiomyogenesis via Gata4 transcription and protein ubiquitination.
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氧化应激通过 Gata4 转录和蛋白泛素化对心肌生成的硬脑膜影响
DOI：
10.1038/s41419-018-0281-y
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发表时间：
2018-02-14
影响因子：
9
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Li T;Zhang X;Jiang K;Liu J;Liu Z
氧化应激产生活性氧（ROS），它可以促进或抑制干细胞的心脏分化，具体取决于刺激的强度以及氧化还原和分化状态的细胞环境。在目前的研究中，我们证实在拟胚体（EB）形成阶段适当强度的过氧化氢有效有利于P19胚胎癌细胞形成自发跳动的心肌细胞。机制研究表明，外源 ROS 增强了 Caspase 介导的 Oct4 和 Nanog 的降解，这两个因素控制多能特性。进一步的实验表明，一组 Nanog 与组蛋白脱乙酰酶 4 (Hdac4) 一起在未分化细胞中建立和维持 Gata4 和 Nkx2.5 的沉默转录状态中发挥着关键作用。因此，过氧化氢的脉冲通过半胱天冬酶依赖性方式耗尽Nanog和Hdac4，以改善对Gata4和Nkx2.5启动子的抑制，从而对心脏分化程序产生持续激活。同时，我们发现过量的ROS激活的JNK级联促进了Gata4蛋白的泛素化和随后的降解。总的来说，我们的结果表明，合适的 ROS 促进转录中 Gata4 的激活，而过量的 ROS 则针对 Gata4 蛋白进行蛋白酶体依赖性降解。 Gata4是平衡氧化应激对心肌生成分化程序的促进和抑制作用的重要调节剂。
Oxidative stress generates reactive oxygen species (ROS) that can promote or inhibit cardiac differentiation of stem cells dependent on the intensity of stimuli as well as cellular context in redox and differentiation status. In the current study, we confirmed that suitable intensity of hydrogen peroxide at the formation stage of embryoid bodies (EBs) effectively favored the formation of spontaneously beating cardiomyocytes from P19 embryonal carcinoma cells. Mechanistic studies implicated that extrinsic ROS enhanced the Caspase-mediated degradation of Oct4 and Nanog, two factors that governing pluripotent property. Further experiments suggested that a cohort of Nanog together with histone deacetylase 4 (Hdac4) played a critical role in establishing and maintaining the silent transcriptional status ofGata4andNkx2.5in undifferentiated cells. Thus, an impulse of hydrogen peroxide depleted Nanog and Hdac4 via a caspase-dependent manner to ameliorate the repression onGata4andNkx2.5 promoters, thereby generating a persistent activation on cardiac differentiation program. Meanwhile, we found that excessive ROS-activated JNK cascade to facilitate the ubiquitination and subsequent degradation of Gata4 protein. Overall, our results indicate that suitable ROS promotes the activation of Gata4 in transcription, while excessive ROS targets Gata4 protein for proteasome-dependent degradation. Gata4 is an important modulator balancing the promoting and inhibitory effects of oxidative stress on differentiation program of cardiomyogenesis.
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影响因子：
4.8
作者：
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