基于TFEB-PGC1α-PPARγ通路探讨天麻钩藤饮改善高血压血管内皮细胞炎症的机制研究

Hypertension has become one of the most serious diseases that endanger human health. At present, the situation of hypertension in our country is grim. Studies have found that vascular endothelial cell inflammation plays an important role in the development of hypertension. Inhibition the inflammatory reaction of endothelial cells and reduction the apoptosis of endothelial cells are an important way to reduce blood pressure. At the same time, studies have found that TFEB-PGC1α-PPARγ is an important channel regulating vascular endothelial cell inflammation. Our preliminary studies have found that Tianma Gouteng Decoction can exert antihypertensive efficacy through PPARγ. Since TFEB and PGC1α are important upstream factors of PPARγ, we propose a scientific hypothesis that Tianma Gouteng Decoction can exert antihypertensive effect by inhibiting the inflammation of vascular endothelial cells through TFEB-PGC1α-PPARγ channel. In this study, in vitro and in vivo, we observed the changes of endothelial cells by overexpressing or interfering with TFEB, respectively, and evaluated the effect of drugs on the vascular endothelium under the overall conditions, in order to confirm that TFEB-PGC1α-PPARγ was the important channel through which Tianma Gouteng Decoction inhibited vascular endothelial cells inflammation to reduce blood pressure. The study will provide experimental evidence for clarifying the antihypertensive mechanism of Tianma Gouteng Decoction, which has important scientific value for revealing the "multi-target effect" of traditional Chinese medicine.

高血压已成为严重危害人类健康的疾病之一，目前我国高血压形势严峻。研究发现，血管内皮细胞炎症在高血压的发生发展中发挥重要作用。抑制内皮细胞炎症反应，减少内皮细胞凋亡，是降低血压的重要途径和首要目标。同时，研究也发现，TFEB-PGC1α-PPARγ是调控血管内皮细胞炎症的重要通道。前期研究发现，天麻钩藤饮能通过PPARγ发挥降压疗效。由于TFEB、PGC1α是PPARγ上游重要的因子，因此，我们提出科学假说：天麻钩藤饮通过TFEB-PGC1α-PPARγ通道抑制血管内皮细胞炎症发挥降压作用。本研究分别通过体外和体内过表达或干扰TFEB技术，观察内皮细胞的变化，及在整体条件下评价药物对血管内皮的影响，证实TFEB-PGC1α-PPARγ是天麻钩藤饮抑制高血压血管内皮细胞炎症的重要通道，为明确天麻钩藤饮的降压机制提供实验依据，对于揭示中药“多靶点效应”具有重要科研价值。

研究目的：通过AngII诱导的高血压小鼠观察天麻钩藤饮（TGD）对高血压及心血管的作用，进而探讨TFEB在TGD对AngII诱导的高血压小鼠的降压及心血管保护中的作用机制。探寻天麻钩藤饮的主要成分天麻素（GAS）和钩藤碱（RHY）配伍对AngII诱导的小鼠主动脉内皮细胞（MAECs）的影响及TFEB在其中发挥作用的机制。.研究结果：①TGD能够降低AngII诱导的高血压小鼠的血压并发挥心血管保护作用，这与血管舒缩因子的改变有关。②TGD通过TFEB核易位激活下游靶基因的转录，降低炎症因子和增加抗氧化因子的水平。③TFEB过表达会抑制AngII诱导的高血压小鼠的血压升高和心血管损害，并且TGD治疗会协同增加其效果，这与TFEB-PGC-1α-PPARγ调控下的炎症因子和抗氧化基因的改变有关。④TFEB敲低会加剧AngII诱导的高血压小鼠的血压升高和心血管损害，并且给予TGD治疗并无改善，这与TFEB敲低后抑制TFEB-PGC-1α-PPARγ调控下的炎症因子和抗氧化基因的改变有关，说明TFEB是TGD发挥降压及心血管保护的重要靶点。⑤GAS和RHY配伍可减轻AngII诱导的MAECs的细胞功能减退、氧化应激和炎症。TFEB敲减后GAS和RHY配伍对AngII诱导的MAECs的细胞无明显的保护作用。说明GAS+RHY配伍减轻AngII诱导的MAECs的细胞功能减退、氧化应激和炎症是通过TFEB介导的。.研究结论：TFEB是TGD发挥作用的重要靶点，TGD进而能够通过调节TFEB-PGC1α-PPARγ通道，调控血管内皮细胞炎症，来发挥降压作用和心血管的保护作用。