Department of Cardiac Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China.
Department of Electrocardiogram, The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, China.
Int J Biol Sci. 2022 Feb 7;18(4):1651-1662. doi: 10.7150/ijbs.63297. eCollection 2022.
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.
心肌缺血/再灌注（I/R）损伤被认为是全球范围内导致死亡的主要原因。然而，这一过程中涉及的分子机制仍不完全清楚。我们之前的研究报告表明，Notch1 和 Keap1-NRF2 信号通路的联合作用可以显著提高心肌细胞的活性，抑制心肌细胞凋亡，减少活性氧的形成，提高新生大鼠心肌细胞的抗氧化活性。然而，Notch1 信号通路对 NRF2 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 Notch1 通过 RBP-Jκ 依赖性方式激活 Keap-NRF2 信号通路，从而通过抑制线粒体 ROS 的产生来保护心脏免受 I/R 损伤，并改善体外和体内的线粒体生物能量。这些结果表明，Keap-NRF2 信号通路可能成为治疗心肌 I/R 损伤的一种有前途的治疗策略。
