Guang'anmen Hospital, China Academy of Chinese Medical Sciences, 5 Beixiange, Xicheng District, Beijing 100053, China.
Guang'anmen Hospital, China Academy of Chinese Medical Sciences, 5 Beixiange, Xicheng District, Beijing 100053, China.
Phytomedicine. 2024 Sep;132:155331. doi: 10.1016/j.phymed.2023.155331. Epub 2023 Dec 30.
Zishenhuoxue decoction (ZSHX), a Chinese herbal medicine, exhibits myocardial and vascular endothelial protective properties. The intricate regulatory mechanisms underlying myocardial ischemic injury and its association with dysfunctional mitochondrial quality surveillance (MQS) remain elusive.
HYPOTHESIS/PURPOSE: To study the protective effect of ZSHX on ischemic myocardial injury in mice using a TMBIM6 gene-modified animal model and mitochondrial quality control-related experiments.
Using model animals and myocardial infarction surgery-induced ischemic myocardial injury TMBIM6 gene-modified mouse models, the pharmacological activity of ZSHX in inhibiting ischemic myocardial injury and mitochondrial homeostasis disorder in vivo was tested.
Our focal point entailed scrutinizing the impact of ZSHX on ischemic myocardial impairment through the prism of TMBIM6. This endeavor was undertaken utilizing mice characterized by heart-specific TMBIM6 knockout (TMBIM6) and their counterparts, the TMBIM6 transgenic (TMBIM6) and VDAC1 transgenic (VDAC1) mice.
ZSHX demonstrated dose-dependent effectiveness in mitigating ischemic myocardial injury and enhancing mitochondrial integrity. TMBIM6 hindered ZSHX's cardio-therapeutic and mitochondrial protective effects, while ZSHX's benefits persisted in TMBIM6 mice. TMBIM6 also blocked ZSHX's regulation of mitochondrial function in HR-treated cardiomyocytes. Hypoxia disrupted the MQS in cardiomyocytes, including calcium overload, excessive fission, mitophagy issues, and disrupted biosynthesis. ZSHX counteracted these effects, thereby normalizing MQS and inhibiting calcium overload and cardiomyocyte necroptosis. Our results also showed that hypoxia-induced TMBIM6 blockade resulted in the over-activation of VDAC1, a major mitochondrial calcium uptake pathway, while ZSHX could increase the expression of TMBIM6 and inhibit VDAC1-mediated calcium overload and MQS abnormalities.
Our findings suggest that ZSHX regulates mitochondrial calcium homeostasis and MQS abnormalities through a TMBIM6-VDAC1 interaction mechanism, which helps to treat ischemic myocardial injury and provides myocardial protection. This study also offers insights for the clinical translation and application of mitochondrial-targeted drugs in cardiomyocytess.
滋肾活血汤（ZSHX）是一种中药，具有心肌和血管内皮保护作用。心肌缺血损伤的复杂调节机制及其与功能失调的线粒体质量监控（MQS）的关系仍不清楚。
假设/目的：使用 TMBIM6 基因修饰动物模型和与线粒体质量控制相关的实验研究 ZSHX 对缺血性心肌损伤的保护作用。
使用模型动物和心肌梗死手术诱导的缺血性心肌损伤 TMBIM6 基因修饰小鼠模型，测试 ZSHX 在体内抑制缺血性心肌损伤和线粒体动态平衡紊乱的药理活性。
我们的重点是通过 TMBIM6 研究 ZSHX 对缺血性心肌损伤的影响。这项研究使用心脏特异性 TMBIM6 敲除（TMBIM6）小鼠及其 TMBIM6 转基因（TMBIM6）和 VDAC1 转基因（VDAC1）小鼠作为模型动物。
ZSHX 表现出剂量依赖性减轻缺血性心肌损伤和增强线粒体完整性的作用。TMBIM6 阻止了 ZSHX 的心脏治疗和线粒体保护作用，而 ZSHX 的益处在 TMBIM6 小鼠中仍然存在。TMBIM6 还阻断了 ZSHX 对 HR 处理的心肌细胞中线粒体功能的调节。缺氧破坏了心肌细胞中的 MQS，包括钙超载、过度分裂、噬线粒体问题和生物合成受损。ZSHX 对抗了这些作用，从而使 MQS 正常化并抑制钙超载和心肌细胞坏死。我们的结果还表明，缺氧诱导的 TMBIM6 阻断导致主要的线粒体钙摄取途径 VDAC1 的过度激活，而 ZSHX 可以增加 TMBIM6 的表达并抑制 VDAC1 介导的钙超载和 MQS 异常。
我们的研究结果表明，ZSHX 通过 TMBIM6-VDAC1 相互作用机制调节线粒体钙稳态和 MQS 异常，有助于治疗缺血性心肌损伤并提供心肌保护。这项研究还为线粒体靶向药物在心肌细胞中的临床转化和应用提供了见解。
