益气活血中药对慢性间歇性低氧复合胰岛素抵抗介导的动脉粥样硬化过程中SREBP-1c/FAS通路的影响

Obstructive sleep apnea hypopnea syndrome(OSAHS) causes chronic intermittent hypoxia(CIH), which can lead to insulin resistance(IR) and formation of glucose and lipid metabolic disorder. The synergy of CIH and IR can promote vascular endothelial injury and cause OSAHS related atherosclerosis (AS) and occurrence of other vascular lesions. Studies have found that SREBP-1c/FAS signaling pathway plays an important role in the process of CIH and IR mediated vascular endothelial injury. Vascular endothelial injury and atherosclerosis have close relationship with “Qi deficiency and blood stasis” of traditional Chinese medicine. Previous study suggests that Chinese herbal medicine for nourishing Qi and removing blood stasis have the effects of anti-imflammatory, IR- improving, and other vascular endothelial protective effects. Whether the mechanism of these functions is realized by regulating SREBP-1c/FAS signaling pathway has not been reported. This study intends to build a model system of CIH and IR. 3T3-L1 cells will be treated by the high sugar and high insulin method in vitro, while ApoE-/- mice will be treated with streptozocin and high-fat diet to build IR and AS model in vivo. Both of cell model and animal model will be treated by the CIH stimulation. To make clear of the vascular endothelial protective effect of Chinese herbal medicine for nourishing Qi and removing blood stasis, the molecular mechanism about SREBP-1c/FAS signaling pathway will be studied. The aim of our study is to provide experimental evidence for the clinical application of Chinese herbal medicine in the treatment of OSAHS related AS.

阻塞性睡眠呼吸暂停综合征（OSAHS）导致的慢性间歇性低氧（CIH）可引起胰岛素抵抗（IR）及糖脂代谢紊乱。CIH与IR协同能促进血管内皮损伤及OSAHS继发动脉粥样硬化（AS）的发生。研究发现SREBP-1c/FAS通路可能在CIH复合IR介导的动脉粥样硬化过程中扮演了重要角色。血管内皮损伤及AS与中医“气虚血瘀”密切相关，前期研究显示益气活血中药具有抗炎、改善IR等血管内皮保护效应而适用于OSAHS继发AS的治疗，但其作用机制是否通过调控SREBP-1c/FAS通路未见报道。本研究拟构建CIH复合IR模型体系，体外通过高糖法建立IR脂肪细胞模型，体内以链脲佐菌素合并高脂饲料诱导ApoE基因敲除小鼠建立IR动脉粥样硬化动物模型，复合CIH刺激，以SREBP-1c/FAS通路为切入点，阐明益气活血中药血管内皮保护效应的分子机制，为益气活血中药防治OSAHS继发AS的临床应用提供实验证据。

阻塞性睡眠呼吸暂停综合征（OSAHS）导致的慢性间歇性低氧（CIH）可引起胰岛素抵抗（IR）及糖脂代谢紊乱，而CIH与IR协同能促进血管内皮损伤及OSAHS继发动脉粥样硬化（AS）的发生。研究发现SREBP-1c/FAS通路可能在CIH复合IR介导的动脉粥样硬化过程中扮演了重要角色。前期研究显示益气活血中药具有抗炎、改善IR等血管内皮保护效应而适用于OSAHS继发AS的治疗，但其作用机制是否通过调控SREBP-1c/ FAS通路未见报道。本研究分别于体内外建立间歇性低氧（IH）复合IR的细胞模型及CIH复合IR的ApoE-/-小鼠AS模型，以SREBP-1c/FAS通路为切入点，观察益气活血中药的干预效应及SREBP-1c/FAS信号通路在其中的作用。研究发现，在体外细胞水平，益气活血中药能抑制IH引起的SREBP-1、FAS蛋白表达水平上调，P<0.05。在体内动物水平，益气活血中药可降低LDL-C、CRP水平，升高HDL-C、SOD水平，降低TNF-α、VCAM-1的mRNA及蛋白表达水平，降低主动脉、骨骼肌SREBP-1c、FAS mRNA及蛋白表达水平，降低主动脉、肝组织HIF-1α mRNA及蛋白表达水平、IRS-1mRNA，减小AS斑块。在体研究表明，益气活血中药可通过调控SREBP-1c/FAS信号通路的表达，显著降低炎症、氧化应激和血脂水平，从而延缓AS的进展，减少心血管事件的发生。本研究阐明了益气活血中药血管内皮保护效应的分子机制，为其防治OSAHS继发AS的临床应用提供实验证据。