目的 探讨苓桂术甘汤（Linggui Zhugan Decoction，LGZGD）通过调控线粒体钙单向转运体（mitochondrial calcium uniporter，MCU）-线粒体钙（mitochondrial calcium，mtCa²⁺）通路介导的线粒体自噬，改善心肌梗死（myocardial infarction，MI）后心力衰竭（heart failure，HF）的分子机制。方法 构建大鼠MI后HF模型及H₂O₂诱导的H9c2心肌细胞损伤模型，设置假手术组、模型组、LGZGD组和卡托普利组，并结合MCU敲低或过表达进行干预；采用超声心动图、Masson染色、透射电子显微镜分别检测大鼠心功能、心肌纤维化程度、线粒体超微结构，通过qRT-PCR、Western blotting检测线粒体自噬及线粒体功能相关基因和蛋白的表达水平，检测活性氧（reactive oxygen species，ROS）、mtCa²⁺水平并定量分析心肌损伤标志物，利用共聚焦显微镜观察细胞自噬流变化。结果 与假手术组比较，MI后HF大鼠心功能显著下降，心肌纤维化和线粒体损伤加重，线粒体自噬相关基因转录失调，MCU转录水平显著上调（P＜0.001）；H₂O₂诱导的H9c2细胞ROS、mtCa²⁺水平显著升高，自噬流受阻，心肌损伤标志物水平显著上升（P＜0.01）。与模型组比较，LGZGD组可显著改善MI后HF大鼠心功能，减轻心肌纤维化和线粒体损伤，下调MCU表达（P＜0.01），调控自噬及线粒体自噬相关基因表达（P＜0.05、0.01）；细胞水平上LGZGD可降低H₂O₂诱导的H9c2细胞ROS、mtCa²⁺水平，恢复线粒体形态和自噬流，降低心肌损伤标志物水平（P＜0.01）。MCU敲低可增强LGZGD的心脏保护效果，MCU过表达则加剧细胞损伤，LGZGD可有效逆转MCU过表达造成的细胞损伤，并改善氧化应激相关酶紊乱（P＜0.05、0.01）。结论 LGZGD通过恢复MCU-mtCa²⁺稳态、促进线粒体自噬流，减轻氧化应激损伤，改善MI后HF。

Objective To investigate the molecular mechanism by which Linggui Zhugan Decoction (苓桂术甘汤, LGZGD) ameliorates heart failure (HF) after myocardial infarction (MI) via regulating mitophagy mediated by mitochondrial calcium uniporter (MCU)-mitochondrial calcium (mtCa²⁺) signaling pathway. Methods Rat models of post-MI HF and hydrogen peroxide (H₂O₂)-induced H9c2 cardiomyocyte injury models were established. For in vivo experiments, rats were assigned to sham group, model group, LGZGD group and captopril group. For in vitro experiments, H9c2 cells were divided into corresponding groups with additional interventions of MCU knockdown or overexpression. Echocardiography, Masson staining and transmission electron microscopy were performed to evaluate rat cardiac function, myocardial fibrosis and mitochondrial ultrastructure, respectively. The mRNA and protein expression levels of genes related to mitophagy and mitochondrial function were detected by qRT-PCR and Western blotting. The levels of reactive oxygen species (ROS) and mtCa²⁺ were measured, myocardial injury markers were quantitatively analyzed, and changes in cellular autophagic flux were observed using confocal laser scanning microscopy. Results Compared with sham group, rats with post-MI HF exhibited significantly impaired cardiac function, aggravated myocardial fibrosis and mitochondrial damage, dysregulated transcription of mitophagy-related genes, and markedly upregulated MCU transcription level (P < 0.001). In H₂O₂-stimulated H9c2 cells, ROS and mtCa²⁺ levels were significantly increased, autophagic flux was blocked, and myocardial injury marker levels were notably elevated (P < 0.01).Compared with model group, LGZGD treatment significantly improved cardiac function, alleviated myocardial fibrosis and mitochondrial damage, downregulated MCU expression (P < 0.01), regulated the mRNA expressions of autophagy and mitophagy-related genes in post-MI HF rats (P < 0.05, 0.01). At the cellular level, LGZGD reduced ROS and mtCa²⁺ levels in H₂O₂-injured H9c2 cells, restored mitochondrial morphology and autophagic flux, and decreased myocardial injury marker levels (P < 0.01). MCU knockdown enhanced the cardioprotective effect of LGZGD, whereas MCU overexpression exacerbated cellular injury. LGZGD effectively reversed MCU overexpression-induced cellular damage and ameliorated the dysregulation of oxidative stress-related enzymes (P < 0.05, 0.01). Conclusions LGZGD alleviates oxidative stress injury and improves post-MI heart failure by restoring MCU-mtCa²⁺ homeostasis and promoting mitochondrial autophagic flux.

R285.5

国家自然科学基金资助项目（81973844）；安徽省重点研究与开发计划项目（201904a07020109）；安徽中医药大学研究生科技创新基金资助项目（2021ZC09）；黄金玲安徽省名中医工作室（2025）