AMPK/PKA通过HDAC5-KLF2对内毒素诱导的血管内皮细胞炎症反应的调节作用机制研究

血管内皮细胞通过参与调节白细胞向组织浸润和血管通透性，在脓毒症早期诱发的多器官功能损伤中起着重要作用。在脓毒症中，组蛋白去乙酰化酶 (HDACs)的活性显著增强。转录因子KLF2作为细胞固有免疫反应的负调节蛋白，在维持内皮细胞功能方面具有重要的作用。KLF2的转录活性受HDAC5去乙酰基化活性的调控。作为HDAC5的上游蛋白激酶，AMPK和PKA通过磷酸化HDAC5的不同位点 (S259/S498/S280)调节其在细胞核内的去乙酰化活性，进而对细胞功能进行调控。但到目前为止，脓毒症中蛋白激酶AMPK和PKA的活化程度及其对内皮细胞炎症反应的调节作用机制尚不明确。因此，本研究拟在体外和体内通过干预蛋白激酶AMPK和PKA的活性，探讨AMPK/PKA通过HDAC5-KLF2对内毒素诱导的内皮细胞炎症反应以及器官功能损伤的调节作用，为脓毒症的早期抗炎治疗提供新型靶标。

Vascular endothelial cells, by involving in the modulation of leukocyte transmigration and vascular permeability, play a pivotal role in sepsis-induced multiple organ dysfunction. The activity of histone deacetylases (HDACs) is significantly enhanced in sepsis. Transcription factor KLF2 (Krueppel-like factor 2), as the negative regulator of endothelial inflammatory responses , plays an important role in maintaining endothelial functions. The expression and transcriptional activity of KLF2 is regulated by HDAC5. As the upstream protein kinases, AMPK and PKA modulate the deacetylation activity of HDAC5 by phosphorylating its specific sites (S259/S498/S280)，leading to the regulation of cellular functions. However, till now, the activity of AMPK and PKA in sepsis and their regulatory mechanisms of endothelial inflammation are not elucidated yet. Therefore, this study, by interfering AMPK and PKA activities, aims to investigate the regulatory mechanism of AMPK/PKA-HDAC5-KLF2 in regulating endotoxin-induced endothelial inflammatory responses and organ injury both in vitro and in vivo, providing potentially new therapeutic targets for the anti-inflammatory therapy in the early stage of sepsis.