NF-κB/p53/Drp1调控线粒体分裂在代谢应激所致血管内皮损伤的分子机制研究

Vascular endothelial cell damage induced by metabolic stress is an initial factor of atherosclerosis. Our early studies found that NF-κB signaling pathway was the key mediator of vascular endothelial cell injury induced by oxidative stress, and our preliminary data also showed that metabolic stress increased mitochondrial fission, endothelial dysfunction and apoptosis, and the expression of Drp1 was elevated and NF-κB signaling pathway was activated. But the molecular mechanism that NF-κB signaling modulates mitochondria fission is still unclear. NF-κB plays its biological function in regulating IKK→IκBα→p65/p50→p53→target genes pathway, while p53 is an important molecule in regulating mitochondria energy metabolism, including the expression of Drp1. Therefore, we assumed that NF-κB/p53/Drp1 cascade reaction may take part in the vascular endothelial cell damage induced by metabolic stress through regulating mitochondria fission. This study has three parts: ①to test if NF-κB/p53/Drp1 cascade reaction exists in the vascular endothelial cell under metabolic stress. ②if NF-κB/p53/Drp1 cascade reaction take part in vascular endothelial cell damage through mitochondrial fission. ③to test if target intervention of NF-κB/p53/Drp1 pathway can alleviate or reverse the vascular endothelial cell injury.

代谢应激所致血管内皮细胞早期损伤是动脉粥样硬化发生的重要始动因素。课题组前期证实NF-κB通路是介导氧化应激所致血管内皮细胞损伤的关键，预实验也显示：代谢应激诱导血管内皮细胞线粒体过度分裂、功能障碍和细胞凋亡显著增加；线粒体分裂蛋白Drp1明显上调，NF-κB显著激活，但NF-κB通路是如何调控线粒体分裂的机制尚不清楚。NF-κB通路通过IKK→IκBα→p65/p50→p53→靶基因途径发挥分子调控作用，其中p53又是调节线粒体能量代谢的重要分子，可直接影响Drp1表达。因此我们假设：NF-κB/p53/Drp1可能轴向调控线粒体分裂介导代谢应激所致血管内皮细胞损伤。本项目拟包括三个研究部分：①代谢应激状态下血管内皮细胞中是否存在NF-κB/p53/Drp1轴向通路；②该通路是否通过调控线粒体分裂参与血管内皮细胞损伤；③靶向干预该通路是否具有减轻或逆转血管内皮细胞损伤的作用。

研究发现代谢应激激活NF-κB/p53/Drp1轴向通路，能够引起线粒体膜电位Δψm降低、ROS生成增加；促使炎症因子IL-6、IL-8、TNF-α表达增加；胞质中Bax向线粒体移位、细胞色素C（Cyt C）释放激活Caspase细胞凋亡途径，导致线粒体功能障碍、炎性反应增加、细胞凋亡，最终启动AS发生。阐明了IkBa靶向抑制NF-кB通路可能通过降低主动脉内皮细胞中线粒体分裂保护血管内皮功能，从而延缓AS斑块形成，敲除P53蛋白后，这种血管保护作用消失，提示NF-кB通路介导的内皮细胞损伤是AS的早期防治重要干预靶点，其抑制NF-кB抗动脉硬化作用是通过P53-DRP1轴向通路实现的。靶向干预NF-κB/p53/Drp1轴向通路，抑制代谢应激诱导的NF-κB信号通路激活，上调p53表达，降低Drp1表达，抑制细胞线粒体过度分裂，最终减轻细胞损伤，延缓AS发生。

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