三七中原人参二醇型和原人参三醇型皂苷抗动脉粥样硬化作用及其机制研究

Atherosclerosis is the underlying pathology of cardiovascular diseases (CVD), the leading cause of death worldwide. Panax notoginseng and its preparations have been traditionally applied to clinic for the prevention and treatment of CVD. The therapeutical effect attributes to P. notoginseng saponins (PNS), which could be classified into 20(S)-protopanaxatriol (PTS) and 20(S)-protopanaxadiol saponins (PDS) according to their skeleton of their aglycones. Our previous in vivo study has demonstrated that PNS notably decreased the formation of atherosclerotic plague in the apoE-/- mice fed high-fat diet, and the in vitro study showed that PDS exhibit the more potent effect on anti-vascular inflammation, comparing to PTS and PNS. Therefore, a long-term goal of present proposal is to evaluate and compare the anti-atherosclerotic effects of PTS and PDS in apoE-/- mice fed high-fat and high-cholestrol diet using an en-face method for plaque evaluation, and to elucidate the underlying mechanisms involving NF-κB and MAPK pathway-based vascular inflammation. Finally, using UPLC/Q-TOFMS-based metabolomics approaches, the metabolic biomarkers of atherosclerosis will be identified, and which metabolic pathway intervened by PTS and PDS in the prevention of atherosclerosis will be also investigated in order to reveal their underlying mechnisams from metabolic aspect. Our findings of present proposal will provide the scientific evidence for the development of new class potential anti-atherogenic drugs from P. notoginseng.

以动脉粥样硬化为基础的心脑血管疾病严重危害人类健康，中药三七总皂苷（PNS）及其制剂抗动脉粥样硬化的效果较为明确，根据分子母核不同，PNS可分为原人参三醇型皂苷（PTS）和原人参二醇型皂苷（PDS）。前期工作观察到：PNS能显著减少高脂饮食诱导的apoE缺陷小鼠动脉粥样硬化的形成；体外实验表明PDS表现比PNS和PTS更强的抗血管炎症活性，提示PDS可能在体内具有更好的抗动脉粥样硬化效果。本项目利用高脂诱导的apoE缺陷小鼠模型及客观的en-face斑块评价手段，在体内研究并比较PTS和PDS对动脉粥样硬化的影响，从NF-κB和MAPK信号通路进行血管炎症作用机制的阐述。并且利用UPLC/Q-TOFMS代谢组学技术，从干预代谢的角度，进一步研究PDS 和PTS 抗动脉粥样硬化作用机制及相关代谢通路的影响。本项目研究成果将为从中药三七中开发新型的抗动脉粥样硬化药物提供科学依据。

以动脉粥样硬化为基础的心脑血管疾病严重危害人类健康，中药三七总皂苷（PNS）及其制剂抗动脉粥样硬化的效果较为明确，根据分子母核不同，PNS可分为原人参三醇型皂苷（PTS）和原人参二醇型皂苷（PDS）。前期工作观察到：PNS能显著减少高脂饮食诱导的apoE缺陷小鼠动脉粥样硬化的形成。研究表明三七PDS和PTS在一些药理活性上表现出不同、甚至截然相反的作用，包括中枢神经系统、血管新生和溶血活性等。体外实验表明PDS表现比PNS和PTS更强的抗血管炎症活性。因此我们假设三七皂苷PDS在整体动物水平上具有更好的抗动脉粥样硬化效果。为了验证这一假说，首先建立了从中药三七中快速分离制备PDS和PTS两类皂苷的方法，所得的皂苷用于后续的药理学实验；再利用高脂诱导的apoE缺陷小鼠模型及客观的en-face斑块评价手段，在小鼠体内研究并比较PTS和PDS对动脉粥样硬化的影响及其可能的机制。研究表明：相比PTS，PDS对于高脂饮食诱导apoE小鼠的动脉粥样硬化有更佳的保护作用，具体体现在能够减少主动脉斑块的形成，降低血脂水平，降低血管局部炎症因子表达和巨噬细胞的浸润，并促进稳固斑块的血管平滑肌细胞聚集。其保护机制可能与抗血管炎症有关，具体表现为抑制血管内皮细胞的ICAM、VCAM表达、减低单核细胞的黏附以及抑制NF-κB通路中活性转录因子p65的表达和入核。本项目的研究成果将为从中药三七中开发新型的抗动脉粥样硬化药物提供科学依据。