养阴益气活血法抑制代谢记忆对大血管区域免疫炎症微环境的调控研究

Undering the influence of metabolic memory, the intervention which is focus on controling of blood glucose is difficult to prevent diabetic macrovascular injury, and 80% of diabetic patients died of macrovascular disease. How to correctly understand and prevent metabolic memory is the key to prevention and treatment of diabetic macroangiopathy. Chronic inflammation is an important factor in the composition of metabolic memory, the microenvironmental disorder of macrovascular regional immunization inflammation directly leads to vascular injury. From the theory of traditional Chinese medicine, we believe that the process of diabetes metabolic memory , lacking of vital qi, resulting in the production of turbidity and static blood pathogen directly reflected the microenvironment disorders of macrovascular regional immunization inflammation. The clinical effective Shenqi compound recipe with the function of nourishing yin-benefiting qi-activating blood can strengthen qi to eliminate pathogenic factor. The pre-five national natural fund have revealed its role in inhibiting metabolic memory by improving chronic inflammation of diabetes and modulating immunity by methylation. To further explain the mechanism of nourishing yin-benefiting qi-activating blood method inhibiting metabolic memory by regulating the immunization, this project intends to explore the effect of Shenqi compound on macrovascular immunoinflammatory microenvironment from the regulation of lncRNA upstream of methylation, to the downstream cellular immune factor Change, in order to provide evidence for the clinical application of nourishing yin-benefiting qi-activating blood method to block diabetic metabolic memory and protect large blood vessels, and to expand the ideas of prevention and treatment of diabetic macroangiopathy.

代谢记忆影响下，以控制血糖为重点的干预难以阻止糖尿病大血管损伤，80%糖尿病患者死于大血管病变。如何正确认识并阻止代谢记忆，是糖尿病大血管病变防治核心。慢性炎症免疫是构成代谢记忆的重要因素，大血管区域免疫炎症微环境紊乱则直接导致了血管损伤。从中医理论出发，我们认为糖尿病代谢记忆过程中机体正气不足，致浊瘀之邪孳生氤氲，直接体现于大血管区域免疫炎症微环境紊乱。临床效方参芪复方养阴益气活血，可扶正剔邪，前期5个国家自然基金支持下，揭示了其改善糖尿病慢性炎症，通过甲基化调控免疫，进而抑制代谢记忆的作用。为进一步阐释养阴益气活血法调控免疫抑制代谢记忆的作用机制，本项目拟通过参芪复方对大血管免疫炎症微环境的影响，从固有免疫到适应性免疫，从甲基化上游lncRNA调控，到下游细胞免疫因子改变，进行系统的微观机制探讨，为临床应用养阴益气活血法阻止糖尿病代谢记忆保护大血管提供证据，拓展糖尿病大血管病变防治思路。

代谢记忆影响下，以控制血糖为重点的干预难以阻止糖尿病大血管损伤，80%糖尿病患者死于大血管病变。如何正确认识并阻止代谢记忆，是糖尿病大血管病变防治核心。慢性炎症免疫是构成代谢记忆的重要因素，大血管区域免疫炎症微环境紊乱则直接导致了血管损伤。本项目拟通过参芪复方对大血管免疫炎症微环境的影响，从固有免疫到适应性免疫，从甲基化上游lncRNA调控，到下游细胞免疫因子改变，进行系统的微观机制探讨，为临床应用养阴益气活血法阻止糖尿病代谢记忆保护大血管提供证据，拓展糖尿病大血管病变防治思路。通过分析干预16周后检测各组大鼠免疫因子水平、免疫细胞分布、胸主动脉高通量基因芯片测序数据，发现参芪复方可能通过纠正免疫因子及免疫细胞的促炎作用，并发挥抗炎因子的抗炎效应，从而调控大血管区域的免疫炎症微环境。并从mRNA/lncRNA表达谱差异入手，发现参芪复方可调控同为差异mRNAs与差异lncRNAs靶基因的Rgs2，Tp53inp1，Best3，Gprin3及Aplnr基因表达，抑制炎症及凋亡，从而防治糖尿病胸主动脉病变，建立了以cGMP/PKG 信号通路及炎症凋亡密切相关的基因为核心的调控网络初步构架。