Keap-NRF2 signaling contributes to the Notch1 protected heart against ischemic reperfusion injury via regulating mitochondrial ROS generation and bioenergetics.
Keap-NRF2 signaling contributes to the Notch1 protected heart against ischemic reperfusion injury via regulating mitochondrial ROS generation and bioenergetics.
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Keap-NRF2 信号通过调节线粒体 ROS 生成和生物能量学有助于 Notch1 保护心脏免受缺血再灌注损伤
DOI：
10.7150/ijbs.63297
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发表时间：
2022
影响因子：
9.2
通讯作者：
Zhou XL
中科院分区：
文献类型：
--
作者：
Xu H;Wan XD;Zhu RR;Liu JL;Liu JC;Zhou XL
心肌缺血/再灌注（I/R）损伤被认为是全世界死亡的主要原因。然而，参与这一过程的分子机制仍然没有完全理解。我们以前报道Notch 1和Keap 1-NRF 2信号通路的联合作用可以显著增加心肌细胞的活性，抑制心肌细胞的凋亡，减少活性氧的形成，提高新生大鼠心肌细胞的抗氧化能力。然而，Notch 1信号通路对NRF 2信号通路的调控机制及其在I/R损伤中的实际作用尚不清楚。在此，我们发现Notch 1以RBP-Jκ依赖的方式激活Keap-NRF 2信号通路，从而通过抑制线粒体ROS的产生保护心脏免受I/R损伤，并在体外和体内改善线粒体生物能量学。这些结果表明，Keap-NRF 2信号转导可能成为治疗心肌I/R损伤的有前途的治疗策略。
Myocardial ischemia/reperfusion (I/R) injury is recognized as the leading cause of death worldwide. However, the molecular mechanisms involved in this process are still not fully understood. We previously reported that the combined action of Notch1 and Keap1-NRF2 signaling pathway can significantly increase the activity of cardiomyocytes, inhibit the apoptosis of cardiomyocytes, reduce the formation of reactive oxygen species, and improve the antioxidant activity in neonate rat myocardial cells. However, the regulatory mechanism of Notch1 signaling pathway on the NRF2 signaling pathway and its actual role on I/R injury are still unclear. Herein, we found that Keap-NRF2 signaling is activated by Notch1 in RBP-Jκ dependent manner, thus protects the heart against I/R injury via inhibiting the mitochondrial ROS generation and improves the mitochondrial bioenergetics in vitro and in vivo. These results suggest that Keap-NRF2 signaling might become a promising therapeutic strategy for treating myocardial I/R injury.
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