基于“阳微阴弦”理论的瓜蒌薤白半夏汤调控P2X7R/NLRP3改善缺血心肌交感神经重构的效应机制

Cardiac sympathetic remodeling, which is lack of effective treatments, is an important step of pathological development after myocardial ischemia injury. GualouXiebaiBanxia Decoction has exhibited obvious clinical advantages based on the TCM theory of “weak pulse at YANG and stringy pulse at YIN” and the idea of “combination of disease and syndrome”. The goal of this project is to explore the key mechanism of preventing sympathetic remodeling based on researching from the multi targets and integration effects of GualouXiebaiBanxia Decoction. Our preliminary works show that GualouXiebaiBanxia Decoction prevents the sympathetic remodeling and improves cardiac function in myocardial ischemia injury model, and the effective component Quercetin inhibits the activation of microglia and reduces the expression of P2X7R and IL-1 beta. Based on the above opinions and the new progress of sympathetic remodeling mediated by abnormal activation of P2X7R/ NLRP3/IL-1β in myocardial ischemia, the following hypothesis is raised: GualouXiebaiBanxia Decoction and its components can reverse sympathetic remodeling and improve the progress of cardiac function and arrhythmia susceptibility after myocardial ischemia, through targeting the P2X7R/NLRP3/IL-1 beta and its downstream molecules of macrophage and microglia in the paraventricular nucleus. Molecular biology, immunology, and analytical chemistry methods will be used to observe key molecules effect, and pharmacokinetic characteristics of GualouXiebaiBanxia Decoction in treatment of sympathetic remodeling from the levels of the whole, tissue, cellular and molecular genes, which taking compound- compatibility- composition as the main line. The project is expected to provide new clues and potential targets for clinical application and drug development.

心肌交感神经重构是缺血损伤后的重要病理环节，缺乏有效防治措施。从阳微阴弦理论和病证结合思路，应用瓜蒌薤白半夏汤干预具有较好临床优势。如何从该复方的多靶点整合效应揭示其防治交感重构的关键机制，是本项目的目标。前期工作发现，瓜蒌薤白半夏汤可逆转心肌缺血模型的交感增生并改善心功能，其有效组分槲皮素可抑制小胶质细胞活化并降低P2X7R和IL-1β表达。基于以上认识，结合心肌损伤P2X7R/NLRP3/IL-1β异常活化介导交感重构的新进展，提出假说：瓜蒌薤白半夏汤通过靶向巨噬细胞和室旁核小胶质细胞的P2X7R/NLRP3/IL-1β及其下游分子，逆转缺血心肌的交感重构，改善心功能恶化和心律失常易感性。将使用分子生物、免疫学和分析化学等方法，从整体、组织、细胞和分子基因等水平，以复方-组分为主线，观察瓜蒌薤白半夏汤防治交感重构的关键机制及药动学特征，以期为临床应用和药物开发提供新的线索和潜在靶点。

缺血性心脏病是一类由于冠状动脉循环障碍而导致心肌供血缺乏的疾病。如何更加有效地挽救心梗后的缺血心肌、防治恶性心律失常形成、改善心功能，仍然是心血管疾病研究领域的严峻挑战。本项目基于《金匮要略》 的“阳微阴弦”病机理论，以及缺血心肌病P2X7R/NLRP3/IL-1β信号介导的交感神经重构机制，研究了具有通阳宣痹效应的瓜蒌薤白半夏汤防治缺血性心脏病心功能恶化和心律失常易感性的效应规律。其中分别使用冠脉结扎心肌梗死模型、异丙肾上腺素结合高脂饮食诱导的心肌损伤病证结合模型、LPS诱导的巨噬细胞活化离体模型、以及血管紧张素II诱导的小胶质细胞活化离体模型，从整体、心脏和神经、细胞和分子水平，观察了瓜蒌薤白半夏汤防治心肌缺血性疾病交感重构的关键分子效应和机制。结果发现瓜蒌薤白半夏汤及其有效组分可以通过巨噬细胞P2X7R/ NLRP3/IL-1β及其下游关键分子逆转缺血心肌的交感神经增生，以及靶向室旁核小胶质细胞的P2X7R/ NLRP3/IL-1β抑制交感神经的异常活动，改善心肌缺血后的心功能恶化和心律失常易感性。该研究项目不仅深入揭示了“阳微阴弦”理论的科学内涵，同时发现了瓜蒌薤白半夏汤防治缺血性心肌病并发症和改善预后的效应机制和应用规律，以及改善缺血心肌的交感神经重构的P2X7R/ NLRP3/IL-1β分子信号途径，为阐明瓜蒌薤白半夏汤防治心肌缺血后交感重构和改善心功能恶化和心律失常易感性的靶向效应和物质基础提供了新的研究证据，并为开发早期干预药物提供了新的研究线索和潜在靶点。