目的 研究麝香通心滴丸（Shexiang Tongxin dropping pills，STDP）通过缓解心肌成纤维细胞的增殖和迁移，从而改善心衰冠脉微血管重构的作用机制。方法 采用大鼠冠脉左前降支结扎建立心衰模型，分为假手术组、模型组、STDP组、替米沙坦（telmisartan，TLM）组，ig给药14 d，通过心脏超声检测心功能，马松染色、天狼猩红染色检测心肌冠脉微血管重构；采用血管紧张素II（angiotensin Ⅱ，Ang Ⅱ）诱导心肌成纤维细胞建立纤维化模型，将细胞分为对照（空白DMEM培养基）组、Ang II（1 μmol/L）组、Ang II（1 μmol/L）＋STDP各剂量组（1.08、2.16、4.32、8.64 mg/kg）和Ang Ⅱ（1 μmol/L）＋血管紧张素转化酶2（angiotensin converting enzyme 2，ACE2）抑制剂MLN-4760（1 μmol/L）组。通过CCK-8法检测心肌成纤维细胞增殖情况，划痕实验检测心肌成纤维细胞迁移情况；免疫印迹（Western blotting，WB）法检测ACE2、血管紧张素II受体2（angiotensinⅡ receptor 2，AT2）、AT1、MAS1癌基因（MAS1 oncogene，MAS1）、血清应答因子（serum response factor，SRF）、胶原蛋白1（collagen 1，COL1）、基质金属蛋白酶2（matrix metalloproteinase 2，MMP2）、骨桥蛋白（osteopontin，OPN）的表达。结果 心脏超声显示STDP可提高心衰大鼠左心室射血分数（left ventricular ejection fraction，EF）、左心室短轴缩短率（left ventricular fractional shortening，FS）和心输出量（P＜0.05）；马松染色、天狼猩红染色结果显示STDP抑制心脏冠脉微血管纤维化（P＜0.05）；CCK-8结果显示STDP可显著降低心肌成纤维细胞增殖（P＜0.05），划痕实验表明STDP可显著抑制心肌成纤维细胞迁移（P＜0.05）。WB结果显示STDP可提高ACE2、AT2和MAS1蛋白表达，抑制AT1、SRF蛋白表达（P＜0.05）；同时，STDP抑制COL1、MMP2和OPN的蛋白表达（P＜0.05），而ACE2抑制剂逆转了STDP的调控作用。结论 STDP通过调控ACE2-AT2/MAS1信号通路和AT1-SRF信号通路抑制心脏冠脉微血管重构，改善心功能异常，防治心梗后心衰。

Objective To investigate mechanism of Shexiang Tongxin dropping pills (麝香通心滴丸, STDP) to improve coronary microvascular remodeling in heart failure by alleviating proliferation and migration of myocardial fibroblasts. Methods A heart failure model was established by ligating the left anterior descending coronary artery in rats, which were divided into sham surgery group, model group, STDP group, and telmisartan (TLM) group for 14 d of treatment. Cardiac function was evaluated by echocardiography, and myocardial coronary microvascular remodeling was detected by Masson and Sirius red staining. Myocardial fibroblasts were induced by angiotensin Ⅱ (Ang Ⅱ) to establish fibrosis model. The cells were divided into control (blank DMEM medium) group, Ang II (1 μmol/L) group, Ang Ⅱ (1 μmol/L) + STDP groups (1.08, 2.16, 4.32, 8.64 mg/kg) and Ang Ⅱ (1 μmol/L) + angiotensin converting enzyme 2 (ACE2) inhibitor MLN-4760 (1 μmol/L) groups. The proliferation of myocardial fibroblasts was detected byCCK-8, and the migration of myocardial fibroblasts was detected by scratch assay. Western blotting (WB) was used to detect the expression levels of pathway proteins such as ACE2, angiotensin II receptor 2 (AT2), AT1, MAS1 oncogene (MAS1), serum response factor (SRF) and migration proteins such as collagen (COL1), matrix metalloproteinase 2 (MMP2), and osteopontin (OPN). Results Echocardiography showed that STDP increased left ventricular ejection fraction (EF), left ventricular fractional shortening (FS) and cardiac output in heart failure rats (P < 0.05). The results of Masson and Sirius red staining showed that STDP inhibited the area of microvascular fibrosis in the coronary arteries of the heart (P < 0.05). The CCK-8 result showed that STDP inhibited the proliferation of myocardial fibroblasts (P < 0.05), and scratch assay showed that STDP inhibited the migration of myocardial fibroblasts (P < 0.05). WB showed that STDP increased the expression levels of ACE2, AT2, and MAS1, while inhibiting the expression levels of AT1 and SRF proteins (P < 0.05). Meanwhile, STDP inhibited the expression levels of COL1, MMP2, OPN and other proteins (P < 0.05), while ACE2 inhibitors reversed the regulatory effect of STDP. Conclusion STDP inhibits coronary microvascular remodeling by regulating ACE2-AT2/MAS1 signaling pathway and AT1-SRF signaling pathway, improves cardiac function, and prevents heart failure after myocardial infarction.

R285.5

国家自然科学基金项目（81930113，82305216）;中国博士后科学基金项目（2023M730345）