中药复方心肌尔康对高血压大鼠Rac1-eNOS/Rac1-NADPH氧化酶信号通路的调控作用

Recent studies have shown that endothelial dysfunction plays an important role in hypertension cardiovascular remodeling, and keep dynamic equilibrium of Rac1/eNOS and Rac1/NADPH oxidase signal pathway to maintain endothelial function is curcial. Our previous studies have demonstrated that Xinjierkang formula ameliorated 2K1C induced hypertension cardiovascular remodeling and target organ injury significantly, and its mechanism may be related to inhibit excessive activation of ROS-ASK-1-NF-κB. In addition, we also found that Xinjierkang formula increased serum NO content and improved endothelail-dependent vascular relaxation. The aim of this study is to isolate and screen the effective components in Xinjierkang formula from entire animal model, organ，cell and molecule level, basing on chemical matteromics theory and related technologies, then effective substance (group) and targeting to Rac1/eNOS and Rac1/NADPH oxidase signal pathway were separated,screening and identified furtherly. Hoping to summarize and consummate the law and regulatory networks of Xinjierkang in anti-hypertension cardiovascular remodeling，providing scientific basis for Xinjierkang in exploring its mechanism systematically and clinical use.

内皮细胞功能紊乱在高血压心血管重构中扮演重要角色，在内皮细胞中Rac1/eNOS和Rac1/NADPH氧化酶的动态平衡对于维持内皮细胞功能至关重要。前期研究结果表明心肌尔康能明显改善2K1C诱导高血压大鼠心血管重构和靶器官损伤，其机制与抑制ROS-ASK-1-NF-κB信号转导通路过度活化有关。此外，还发现心肌尔康能明显提高血浆中NO水平和内皮依赖性血管舒张功能。基于此本研究拟应用化学物质组学理论及相关技术，以药理活性为导向的指导原则，分别在整体、器官、细胞和分子水平筛选心肌尔康靶向作用内皮细胞的有效组分，并对其调控Rac1/eNOS和Rac1/NADPH氧化酶信号转导通路的关键分子进行深入探索。以期总结、完善该方抗高血压心血管重构的规律和调控网络，为心肌尔康抗高血压作用机制的系统研究和应用于临床提供科学依据。

项目背景我们前期的研究结果表明，心肌尔康（XJEK）对疾病动物模型的改善作用至少部分与改善ED（ED）有关。本次研究拟以内皮细胞为研究对象，进一步探讨XJEK的心血管保护作用内皮机制。研究内容 在多个心血管疾病动物模型上，从多方面来探讨XJEK的药效及潜在内皮机制。结果及关键数据 ○1L-NAME诱导高血压小鼠实验结果显示, 经XJEK全方或XJEK多糖治疗4wk后，均能明显改善高血流动力学状态（5373.14±854.29 vs 4479.64±858.25mmHg；5487.19±674.56 vs 4777.74±797.27 mmHg）；XJEK全方能明显抑制心肌组织中eNOS蛋白表达（6.29±2.33 vs 16.67±7.24）。○2XJEK对AngⅡ诱导的人脐静脉内皮细胞损伤实验表明，与AngⅡ组相比，XJEK可剂量依赖性提高内皮细胞活力，增加eNOS蛋白的表达，促进NO释放，降低胞浆内Ca2+浓度。○3XJEK对心肌梗死小鼠量效实验结果显示，与模型组相比，XJEK治疗4周后均能明显改善+dp/dtmax（3356.95±981.36vs3370.54±351.13、4318.40±740.11 4275.33±474.32）；降低血清及心肌组织中Ang-II、ET-1含量。○4XJEK对心肌梗死小鼠时效实验结果显示，与模型组相比，XJEK组在2、4、6周末均能明显抑制HW/BW（3.24±0.11 vs 2.96±0.06； 2.85±0.07 vs 2.57±0.10； 2.79±0.04 vs 2.57±0.07）；提高血清中NO、BH4含量，降低ET-1（2周228.49±9.17 vs 193.87±12.71；4周225.32±8.54 vs 190.42±9.03；6周228.83±8.35 vs 198.22±9.30）及ADMA和Ang-II和NT-ProBNP含量。○5XJEK对高盐诱导高血压小鼠实验结果表明，与模型组相比，XJEK能明显改善HW/BW、LVSP 和+dp/dtmax（5315.25±1122.92 vs 4275.33±474.32），提高NO含量，降低血清及心肌组织中Ang-II、ET-1含量。科学意义 XJEK对多种心血管疾病体内外模型均有改善作用，其机制至少部分与改善ED、降低OS水平、抑制炎症反应有关。