三七皂苷在心肌缺血复合肿瘤病理环境下双向调节新血管生成的作用机制研究

With population growing and aging, the superposition of cancer and coronary heart disease has been posing increased threats to human health. Panax notoginseng saponins (PNS) consist of a number of active components that exhibit dual regulatory effects on promoting or inhibiting angiogenesis, which make the PNS a unique medicinal option for prenventing and treating ischemic disorders, tumor growth and metastasis. However, the underlying mechanisms of these pharmacological activities of PNS are currently faced with many unaddressed questions, which has negative impact on the related application and innvotive drug design based on the specialized actions of PNS. Our present proposal is centered on the interventional effects of PNS and major active components, including ginsenoside Rg1, Rb1, on myocardial ischemia and tumor growth. The activity and the downstream signaling pathways of vascular endothelial growth factor receptors (VEGFRs), Integrins and SHRs, as well as the microRNA expression profile will be further analyzed. The data collected will help to interpret the synergistic effects of different PNS active components on angiogenesis in the context of complex pathological conditions, therefore, will uncover the in-depth mechanisms contributing to the unique action of PNS. This will lay important foundation for further exploration of the molecular mechanisms underlying the dual regulatory effect PNS on angiogenesis. Our study will also provide proof-of-principle promoting the innovative drug design and broadening the rational clinical application of PNS. Ultimately, our findings will faciliate the research on illustrating the complex signaling regulatory mechanisms underlying angiogenesis.

随着人口的增加和老龄化，癌症和冠心病的叠加正在构成对人类健康更大的威胁。三七皂苷由于含有促进或抑制新血管生成双重效应的多种活性成分，从而成为防治缺血性疾病、抗肿瘤和防治肿瘤转移的独特药用资源。然而这种特殊药理活性的机制研究尚存在大量空白，影响其特有疗效的应用及基于此的创新药物设计。本项目以新血管生成为靶点，将三七总皂苷及其主要活性单体人参皂苷Rg1、Rb1干预心肌缺血和肿瘤生长的活性研究相结合，选择血管内皮细胞生长因子受体（VEGFRs）、整合素（Integrins）受体及类固醇激素受体（SHRs）系统活性及其介导的信号通路的变化，结合MicroRNA芯片表达谱，剖析三七皂苷主要活性成分在不同及复杂病理环境下调节新血管生成的协调效应，从而深层次揭示三七皂苷的作用机制，探索其双向调节新血管生成作用的分子生物学内涵，为三七皂苷更广泛、更合理的应用，以及基于三七的创新药物设计提供理论和实验依据。

本项目以中医的理念、中药的特性和现代生命科学的技术手段相结合，以存在共同病理基础“新血管生成”的不同疾病模型即缺血模型与肿瘤模型相结合，以三七及其总皂苷整体的药效研究与活性成分单体的药效研究相结合，以体内与体外实验研究相结合，以全基因组mRNA表达谱与MicroRNA网络调控芯片数据相结合，从相关microRNA、基因表达到信号通路探索，系统研究和剖析了三七皂苷及其主要活性成分在不同病理环境下以及复合病理条件下的作用，皂苷主要活性成分相互间的协调效应和可能的配伍机制，项目研究数据不仅证实了三七皂苷在复合性疾病治疗中的独特优势作用，同时通过高通量miRNA及mRNA两套芯片数据为基础进行的深入的相关信号通路、交叉验证研究，揭示了三七及其总皂苷在缺血与肿瘤复合病理条件下作用的分子生物学内涵，证实了三七总皂苷主要活性成分对于基因的调控的部分可能的协调效应，三七总皂苷及其主要活性成分三七皂苷R1、人参皂苷Rg1和Rb1在心肌缺血复合肿瘤病理环境下显著抑制LLCs肿瘤生长，并显著改善心肌缺血损伤，其双向作用的机制可能与对血管生成双向调节作用有关,此外三七总皂苷及皂苷Rd具有显著的抗肿瘤转移作用，其作用机制可能与调控microRNA-18a介导的Smad2通路相关。三七总皂苷上调E-cadherin、Brms1、Mtss1、Timp2等表达，下调Vimentin、MMP3等表达，其机制可能与改变肿瘤EMT有关。三七总皂苷及其主要成分在独立的急性心肌缺血模型中配伍优势作用的探索揭示，三七皂苷活性组分组合Rg1Rb1R1Rd，Rg1Rb1R1，Rg1Rb1Rd，Rg1R1Rd，Rb1R1Rd对ISO诱导的心肌损伤具有保护作用，能显著抑制心肌纤维化形成 。三七皂苷活性组分组合Rg1Rb1R1Rd，Rg1Rb1R1，Rg1Rb1Rd，Rg1R1Rd，Rb1R1Rd能显著抑制ECM生成相关的Col1a1，Fbn1的mRNA表达。尽管研究仍有待进一步深入，但已获得的数据为三七及其总皂苷制剂更广泛、更合理和安全地应用和服务于临床、以及基于三七的创新药物设计提供了一定的理论和实验依据。