Tianjin University of Traditional Chinese Medicine, No. 10, Poyang Lake Road, West Zone, Tuanbo New City, Jinghai District, Tianjin 301617, PR China.
Tianjin University of Traditional Chinese Medicine, No. 10, Poyang Lake Road, West Zone, Tuanbo New City, Jinghai District, Tianjin 301617, PR China.
Phytomedicine. 2024 Aug;131:155773. doi: 10.1016/j.phymed.2024.155773. Epub 2024 May 27.
The activation of the NLRP3 inflammasome has recently been revealed as a novel pathological mechanism of coronary heart disease (CHD). The Dan-Lou tablets (DLT) is widely used in the clinical treatment of CHD and prescription characterized by multi-component and multi-target regulation. However, the anti-inflammatory mechanism of DLT in the treatment of CHD remains unclear.
This study aimed to evaluate the effect of DLT in the treatment of CHD on the priming and activation of the NLRP3 inflammasome and to investigate the underlying anti-inflammatory mechanisms.
First, CHD rats model were established by a high-fat diet combined with left anterior coronary artery ligation (LADCA) followed by DLT intervention. The therapeutic effect of DLT was evaluated according to cardiac function, lipid level, and cardiac histopathology. Next, data-independent acquisition (DIA) proteomics was used to identify the key differential proteins of DLT intervention in CHD rats, and bioinformatics analysis was performed. Finally, the differentially expressed proteins in the NOD-like signaling pathway were verified based on bioinformatics results, and the priming and activation steps of the NLRP3 inflammasome were detected.
In this study, a high-fat diet combined with LADCA was utilized to generate a CHD model, and DLT alleviated myocardial ischemia injury by inhibiting lipid deposition and inflammatory response. Proteomic studies observed that the RNF31, TXN2, and GBP2 of the NOD-like receptor signaling pathway were verified as the key targets of DLT in inhibiting myocardial injury in CHD rats. Furthermore, DLT in the treatment of CHD rats may function through the downregulation of P2X7R expression, thereby interfering with the priming (TLR4/MyD88/NF-κB) and activation (NLRP3/ASC/Caspase-1) of the NLRP3 inflammasome regulated by HSP90, and may then reduce the release of the IL-1β and IL-18 inflammatory factors to play an anti-myocardial injury effect.
Our findings elucidate a novel mechanism of DLT and provide some new drug evaluation targets and therapeutic strategies for CHD. This study innovatively proposed that DLT further exerts an anti-myocardial injury effect by inhibiting P2X7R expression, thereby interfering with the priming (TLR4/MyD88/NF-κB) and activation (NLRP3/ASC/Caspase-1) of the NLRP3 inflammasome regulated by HSP90, and then downregulates the release of the IL-1β and IL-18 inflammatory factors.
NLRP3 炎性小体的激活最近被揭示为冠心病（CHD）的一种新的病理机制。丹鹿片（DLT）广泛应用于 CHD 的临床治疗，其处方特点是多成分、多靶点调节。然而，DLT 在治疗 CHD 中的抗炎机制尚不清楚。
本研究旨在评估 DLT 治疗 CHD 对 NLRP3 炎性小体的初始激活和激活的影响，并探讨其潜在的抗炎机制。
首先，通过高脂肪饮食联合左前冠状动脉结扎（LADCA）建立 CHD 大鼠模型，然后进行 DLT 干预。根据心脏功能、血脂水平和心脏组织病理学评估 DLT 的治疗效果。接下来，采用无依赖采集（DIA）蛋白质组学技术鉴定 DLT 干预 CHD 大鼠的关键差异蛋白，并进行生物信息学分析。最后，基于生物信息学结果验证 NOD 样信号通路中的差异表达蛋白，并检测 NLRP3 炎性小体的初始激活和激活步骤。
本研究采用高脂肪饮食联合 LADCA 建立 CHD 模型，DLT 通过抑制脂质沉积和炎症反应来减轻心肌缺血损伤。蛋白质组学研究观察到 NOD 样受体信号通路中的 RNF31、TXN2 和 GBP2 被验证为 DLT 抑制 CHD 大鼠心肌损伤的关键靶点。此外，DLT 治疗 CHD 大鼠可能通过下调 P2X7R 表达发挥作用，从而干扰 HSP90 调节的 NLRP3 炎性小体的初始激活（TLR4/MyD88/NF-κB）和激活（NLRP3/ASC/Caspase-1），进而减少 IL-1β和 IL-18 炎性因子的释放，发挥抗心肌损伤作用。
本研究阐明了 DLT 的一种新机制，并为 CHD 提供了一些新的药物评价靶点和治疗策略。本研究创新性地提出，DLT 通过抑制 P2X7R 表达进一步发挥抗心肌损伤作用，从而干扰 HSP90 调节的 NLRP3 炎性小体的初始激活（TLR4/MyD88/NF-κB）和激活（NLRP3/ASC/Caspase-1），进而下调 IL-1β和 IL-18 炎性因子的释放。
