The aim of the work was to investigate the effects of acacetin on endothelial dysfunction and aortic fibrosis in insulin-resistant SHR rats and explore its mechanism. Seven-week-old male spontaneously hypertensive rats (SHR) were selected to establish a rat model of hypertension with insulin resistance induced by 10% fructose. The nuclear factor kappa B p65 (NF-κB p65) and Collagen I were observed by Immunohistochemistry. Immunofluorescence was used to observe estrogen receptor-alpha (ERα), estrogen receptor-beta (ERβ), and G protein-coupled receptor 30 (GPR30). Western blotting was used to detect interleukin (IL-1β), Arginase 2 (ARG2), Nostrin, endothelial nitric oxide synthase (eNOS), TGF-β, Smad3, ERK pathway proteins such as p-c-Raf, p-MEK1/2, p-ERK, ERK, p-P90RSK and p-MSK1. We found that acacetin did have an improvement on endothelial dysfunction and fibrosis. Meanwhile, it was also found to have a significant effect on the level of estrogen in this model by accident. Then, the experiment of uterine weight gain in mice confirmed that acacetin had a certain estrogen-like effect in vivo and played its role through the estrogen receptors pathway. In vitro experience HUVEC cells were stimulated with 30 mM/L glucose and 100 mM/L NaCl for 24 h to establish the endothelial cell injury model. HUVEC cells were treated with 1 μM/L estrogen receptors antagonist (ICI 182780) for 30 min before administration. Cell experiments showed that acacetin could reduce the apoptosis of HUVEC cells, the levels of inflammatory cytokines and the expression of TGF-β, Collagen I and Smad3 in endothelial cell injury model. After treatment with ICI 182780, the improvement of acacetin was significantly reversed. The results showed that acacetin relieved endothelial dysfunction and reduced the aortic fibrosis in insulin-resistant SHR rats by reducing the release of inflammatory factors and improving vasodilatory function through estrogen signaling pathway.

这项工作的目的是研究阿卡西汀对胰岛素抵抗性SHR大鼠的内皮功能障碍和主动脉纤维化的影响，并探讨其机制。选择7周大的雄性自发性高血压大鼠（SHR），建立由10％果糖诱导的胰岛素抵抗的高血压大鼠模型。通过免疫组织化学观察到核因子κBp65（NF-κBp65）和胶原I。免疫荧光法用于观察雌激素受体α（ERα），雌激素受体β（ERβ）和G蛋白偶联受体30（GPR30）。Western印迹用于检测白介素（IL-1β），精氨酸酶2（ARG2），诺斯特汀，内皮型一氧化氮合酶（eNOS），TGF-β，Smad3，ERK途径蛋白如pc-Raf，p-MEK1 / 2， p-ERK，ERK，p-P90RSK和p-MSK1。我们发现阿卡西汀确实改善了内皮功能障碍和纤维化。同时，还偶然发现该模型对雌激素水平有显着影响。然后，通过小鼠子宫增重实验证实，醋氨蝶呤在体内具有一定的雌激素样作用，并通过雌激素受体途径发挥作用。在体外实验中，用30 mM / L葡萄糖和100 mM / L NaCl刺激HUVEC细胞24 h，以建立内皮细胞损伤模型。在给药前，将HUVEC细胞用1μM/ L雌激素受体拮抗剂（ICI 182780）处理30分钟。细胞实验表明，阿卡西汀可降低内皮细胞损伤模型中HUVEC细胞的凋亡，炎性细胞因子水平以及TGF-β，I型胶原和Smad3的表达。用ICI 182780治疗后，阿卡西汀的改善明显逆转。结果表明，阿卡西汀通过减少炎症因子的释放并通过雌激素信号传导途径改善血管舒张功能，从而减轻了胰岛素抵抗性SHR大鼠的内皮功能障碍并降低了主动脉纤维化。