基于Nrf2/ARE-HO-1信号通路研究丹酚酸A治疗压力负荷诱导心肌重塑的作用机制

Nuclear factor Nrf2 is a key factor in oxidative stress in cells, and involved in multiple signaling pathways which relieve the myocardial remodeling. In our previous work, Salvianolic acid A (SAA) was found to significantly inhibit endothelial-mesenchymal transformation (EndMT) in pulmonary artery and improve right ventricle remodeling induced by pressure over-load, which has been proved to be related to Nrf2. The present study aims to evaluate the mechanisms of Nrf2/ARE-HO-1 signal pathway in coronary artery EndMT and left ventricle remodeling on molecular, cellular, isolated organ and animal levels. Furthermore, the possibility of targeting at such pathway using SAA in activation Nrf2 and in the treatment of EndMT, cardiomyocyte hypertrophy, fibroblasts proliferation will be studied to verify the regulation effect of Nrf2/ARE-HO-1 in myocardial remodeling and the potential to be a novel drug target. This project will help to further understand physic and pathologic mechanisms of myocardial remodeling and lay the foundation for the discovery and development of new drug targets for the treatment of related diseases. It will also provide ideas and methods for new drug research and development.

核因子Nrf2是细胞氧化应激反应中的关键因子，通过多种信号途径缓解心肌重塑。课题组前期研究发现，丹酚酸A可显著抑制肺血管内皮细胞间质转化(EndMT)过程，并改善压力负荷诱导的右心重塑，其机制可能与Nrf2相关。本项目拟以Nrf2/ARE-HO-1信号轴为切入点，在分子、细胞、组织和整体动物水平，研究靶向该通路来抑制冠脉EndMT，继而延缓心肌重塑的作用机制，并通过系统评价丹酚酸A对EndMT、心肌细胞肥大、成纤维细胞增殖的作用，来进一步验证该信号通路对心肌重塑的调控机制，诠释靶向于Nrf2/ARE-HO-1信号通路抗EndMT的药物能否成为防治心肌重塑诱导的心力衰竭等心血管疾病药物的新的作用靶点。本项目将有助于进一步了解心肌重塑发生的病理生理机制，为寻找和确证防治心肌重塑相关疾病的潜在药物靶点奠定基础，对发现和研究新型药物提供新思路和新途径。

核因子Nrf2是细胞氧化应激反应中的关键因子，通过多种信号途径缓解心肌重塑。本项目在课题组前期工作基础上，以Nrf2/ARE-HO-1信号通路为切入点，在分子、细胞、组织和整体动物水平，研究了靶向该通路来抑制冠状动脉内皮细胞间质转化（EndMT），继而延缓心肌重塑的作用机制，并通过系统评价丹酚酸A对EndMT、心肌细胞肥大、细胞增殖的作用，发现了丹酚酸A可显著抑制EndMT过程并改善不同机制导致的肺动脉高压等压力负荷诱导的心肌重塑，初步验证了靶向于Nrf2/ARE-HO-1信号通路抗EndMT的药物成为防治心肌重塑诱导的心力衰竭等心血管疾病药物的新的作用靶点。本项目的研究成果解释了压力负荷诱导的心肌重塑发生的病理生理机制，也为寻找和确证防治心肌重塑相关疾病的潜在药物靶点奠定了实验基础，对发现和研究新型药物提供了一条新思路和新途径。