淫羊藿次苷Ⅱ通过RelA-LncRNA H19途径 调控VSMC功能抑制血管负性重塑的机制研究

Negative vascular remodeling has long been a critical issue and an unsolved problem, all the known drugs have poor clinical efficacy. VSMC pathological proliferation and phenotype switching mediated by LncRNA H19 is crucial in negative vascular remodeling. We have found potential binding sites between transcription factor RelA and LncRNA H19 promoter region. We further proved icariside II could reduce RelA expression and inhibit negative vascular remodeling, which indicates icariside II might inhibit negative vascular remodeling through RelA-LncRNA H19 pathway. In the project, both cell and transgenic mice will be used to explore the hypotheses: The relationship between icariside II inhibiting negative vascular remodeling and icariside II regulating expression of RelA as well as LncRNA H19; The molecular basic of RelA-LncRNA H19 pathway and function in negative vascular remodeling; The molecular mechanism and targeting characteristic of icarside II mediating negative vascular remodeling and intervening RelA-LncRNA H19 pathway; This study aimed to illuminate pharmacological mechanism of icariside II preventing negative vascular remodeling with drug, transcription factor and non-coding RNA epigenetic regulation, which has great potential in developing inhibitor of negative vascular remodeling and optimizing therapeutic regimen.

血管负性重塑是人们长期关注但尚未解决的难题，现有药物疗效不佳。LncRNA H19介导 VSMC病理性增殖和表型转化是血管负性重塑的关键，课题组发现转录因子RelA与LncRNA H19启动子存在结合位点；并实验证明淫羊藿次苷II可下调RelA表达，同时抑制血管负性重塑；提示淫羊藿次苷II可能通过干预RelA-LncRNA H19途径抑制血管负性重塑。本项目拟在细胞及转基因鼠水平明确：淫羊藿次苷Ⅱ干预血管负性重塑与调控RelA、LncRNA H19表达的相关性；RelA-LncRNA H19途径构成的分子基础及其在血管负性重塑中的作用；淫羊藿次苷Ⅱ通过RelA-LncRNA H19途径干预血管负性重塑的分子机制及靶向特征；本项目从药物、转录因子、非编码RNA表观遗传调控的三维角度，阐明淫羊藿次苷II抑制血管负性重塑的药理学机制，为发掘血管负性重塑抑制剂、优化此类疾病治疗策略提供新思路。

血管闭塞性疾病导致的组织器官缺血是当今人类死亡主要病因，尽管血管外科开放手术及腔内治疗已取得长足进展，但由于血管负性重塑导致的再狭窄严重影响了其远期疗效，血管负性重塑问题一直是临床治疗的难点，甚至被称作为“血管外科医生的挑战”。因此，寻找血管负性重塑的有效干预手段有重要意义。现代药理学研究发现传统中药淫羊藿抗炎、抗增殖等作用，但其作用机制尚待阐明。药代动力学研究发现，淫羊藿次苷II是淫羊藿在体内的主要代谢产物，因此本项目拟研究淫羊藿次苷II对血管负性重塑的干预作用与机制。项目应用分子生物学、生物信息学、蛋白质组学等方法研究证实：①淫羊藿次苷II具有抑制血管负性重塑的作用；②淫羊藿次苷II抑制血管负性重塑与其调控血管平滑肌细胞增殖、迁移、表型转换的功能有关；③淫羊藿次苷II可通过RelA-H19信号轴调控血管平滑肌细胞功能，进而发挥抑制血管负性重塑的药理学作用。上述研究结果阐述了淫羊藿次苷II抑制血管负性重塑的药理学机制，为发掘新型血管负性重塑抑制剂、优化血管闭塞性疾病治疗策略提供了科学数据与理论依据。同时，淫羊藿为贵州省道地药材，本项目研究成果亦为我省淫羊藿的开发利用提供了新思路。