Wu Xuan, Hou Yun-Long, Wang Tong-Xing, Chang Li-Ping, Zhou Hong-Ru, Wang Ming-Ye, Wu Yi-Ling
Department of Cardiology, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.
Hebei Medical University, No. 361, Zhongshan East Road, Shijiazhuang, 050017, China.
J Mol Histol. 2025 Sep 8;56(5):302. doi: 10.1007/s10735-025-10585-2.
Numerous people experiencing acute myocardial infarction are also experiencing myocardial ischemia-reperfusion injury (MIRI). Pyroptosis is a core mechanism in MIRI. Tongxinluo (TXL) has a significant protective effect on endothelial cell function. This study utilized network pharmacology to investigate how TXL improves ischemia/reperfusion injury through targeting dysfunction of endothelial cells. Network pharmacology analysis identified 40 key targets through which TXL improves I/R by regulating endothelial dysfunction. We administered TXL (1.5 g/kg/d, oral gavage) to C57BL/6 mice for 7 days before inducing I/R injury, and used 400 μg/ml TXL for in vitro H/R injury in HUVECs. We extensively investigated the effects of TXL on pyroptosis in heart tissue and explored the underlying mechanism through biochemical assays, histopathology, and Western blot analysis. Network pharmacology analysis revealed that TXL targets primarily act on pyroptosis and inflammatory pathways. TXL pretreatment significantly improved cardiac function with increased EF% and decreased LVESV and LVEDV compared to the model group. Myocardial enzymes (CK, CKMB, LDH, cTnI) were markedly reduced by TXL pretreatment. TXL significantly decreased IL-18 and IL-1β levels in serum and reduced neutrophil infiltration in the ischemic area. TXL administration notably downregulated the expression of pyroptosis-related factors (NF-κB, NLRP3, cleaved-Caspase1, GSDMD) in both MIRI mouse model and H/R-treated HUVECs. Molecular docking showed that ginsenoside Rg3, a key TXL component, can directly interact with NLRP3 and GSDMD. TXL has a significant protective effect on endothelial cell function during I/R injury through inhibition of pyroptosis via the NLRP3/Caspase-1/GSDMD signaling pathway, preserving microcirculation barrier integrity.
许多急性心肌梗死患者也同时经历心肌缺血再灌注损伤（MIRI）。细胞焦亡是MIRI的核心机制。通心络（TXL）对内皮细胞功能具有显著的保护作用。本研究利用网络药理学探讨TXL如何通过靶向内皮细胞功能障碍来改善缺血/再灌注损伤。网络药理学分析确定了40个关键靶点，TXL通过调节内皮功能障碍来改善缺血/再灌注损伤。在诱导I/R损伤前7天，我们对C57BL/6小鼠给予TXL（1.5 g/kg/d，灌胃），并在体外对人脐静脉内皮细胞（HUVECs）使用400 μg/ml TXL进行缺氧/复氧（H/R）损伤实验。我们广泛研究了TXL对心脏组织中细胞焦亡的影响，并通过生化分析、组织病理学和蛋白质印迹分析探索其潜在机制。网络药理学分析表明，TXL的靶点主要作用于细胞焦亡和炎症途径。与模型组相比，TXL预处理显著改善了心脏功能，射血分数（EF%）增加，左心室舒张末期容积（LVESV）和左心室收缩末期容积（LVEDV）降低。TXL预处理显著降低了心肌酶（肌酸激酶（CK）、肌酸激酶同工酶（CKMB）、乳酸脱氢酶（LDH）、心肌肌钙蛋白I（cTnI））水平。TXL显著降低了血清中白细胞介素-18（IL-18）和白细胞介素-1β（IL-1β）水平，并减少了缺血区域的中性粒细胞浸润。在MIRI小鼠模型和H/R处理的HUVECs中，给予TXL显著下调了细胞焦亡相关因子（核因子κB（NF-κB）、NOD样受体蛋白3（NLRP3）、裂解的半胱天冬酶-1（cleaved-Caspase1）、Gasdermin D（GSDMD））的表达。分子对接显示，TXL的关键成分人参皂苷Rg3可直接与NLRP3和GSDMD相互作用。TXL通过NLRP3/半胱天冬酶-1/GSDMD信号通路抑制细胞焦亡，对I/R损伤期间的内皮细胞功能具有显著保护作用，维持微循环屏障的完整性。
