Abstract：
BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
METHODS: 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 (TMBIM6CKO) and their counterparts, the TMBIM6 transgenic (TMBIM6TG) and VDAC1 transgenic (VDAC1TG) mice.
RESULTS: ZSHX demonstrated dose-dependent effectiveness in mitigating ischemic myocardial injury and enhancing mitochondrial integrity. TMBIM6CKO hindered ZSHX\'s cardio-therapeutic and mitochondrial protective effects, while ZSHX\'s benefits persisted in TMBIM6TG mice. TMBIM6CKO 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
METHODS: 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.
METHODS: 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 (TMBIM6CKO) and their counterparts, the TMBIM6 transgenic (TMBIM6TG) and VDAC1 transgenic (VDAC1TG) mice.
RESULTS: ZSHX demonstrated dose-dependent effectiveness in mitigating ischemic myocardial injury and enhancing mitochondrial integrity. TMBIM6CKO hindered ZSHX\'s cardio-therapeutic and mitochondrial protective effects, while ZSHX\'s benefits persisted in TMBIM6TG mice. TMBIM6CKO 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.
CONCLUSIONS: 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.
摘要：
背景：滋肾活血汤（ZSHX），一种中草药，表现出心肌和血管内皮保护特性。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测（MQS）的关系仍然难以捉摸。
目的：采用TMBIM6基因修饰动物模型和线粒体质量控制相关实验研究ZSHX对小鼠缺血性心肌损伤的保护作用。
方法：采用动物模型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，测试了ZSHX在体内抑制缺血性心肌损伤和线粒体稳态紊乱的药理活性。
方法：我们的研究重点是通过TMBIM6棱镜仔细研究ZSHX对缺血性心肌损害的影响。这项努力是利用以心脏特异性TMBIM6基因敲除（TMBIM6CKO）为特征的小鼠及其对应物进行的。TMBIM6转基因小鼠(TMBIM6TG)和VDAC1转基因小鼠(VDAC1TG)。
结果：ZSHX在减轻缺血性心肌损伤和增强线粒体完整性方面表现出剂量依赖性有效性。TMBIM6CKO阻碍了ZSHX的心脏治疗和线粒体保护作用，而ZSHX的益处在TMBIM6TG小鼠中持续存在。TMBIM6CKO还阻断了ZSHX对HR处理的心肌细胞线粒体功能的调节。缺氧破坏了心肌细胞中的MQS，包括钙超载,过度裂变,线粒体自噬问题,破坏了生物合成.ZSHX抵消了这些影响，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VDAC1的过度激活，VDAC1是一种主要的线粒体钙摄取途径，而ZSHX可以增加TMBIM6的表达并抑制VDAC1介导的钙超载和MQS异常。
结论：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翻译和应用提供了见解。
目的：采用TMBIM6基因修饰动物模型和线粒体质量控制相关实验研究ZSHX对小鼠缺血性心肌损伤的保护作用。
方法：采用动物模型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，测试了ZSHX在体内抑制缺血性心肌损伤和线粒体稳态紊乱的药理活性。
方法：我们的研究重点是通过TMBIM6棱镜仔细研究ZSHX对缺血性心肌损害的影响。这项努力是利用以心脏特异性TMBIM6基因敲除（TMBIM6CKO）为特征的小鼠及其对应物进行的。TMBIM6转基因小鼠(TMBIM6TG)和VDAC1转基因小鼠(VDAC1TG)。
结果：ZSHX在减轻缺血性心肌损伤和增强线粒体完整性方面表现出剂量依赖性有效性。TMBIM6CKO阻碍了ZSHX的心脏治疗和线粒体保护作用，而ZSHX的益处在TMBIM6TG小鼠中持续存在。TMBIM6CKO还阻断了ZSHX对HR处理的心肌细胞线粒体功能的调节。缺氧破坏了心肌细胞中的MQS，包括钙超载,过度裂变,线粒体自噬问题,破坏了生物合成.ZSHX抵消了这些影响，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VDAC1的过度激活，VDAC1是一种主要的线粒体钙摄取途径，而ZSHX可以增加TMBIM6的表达并抑制VDAC1介导的钙超载和MQS异常。
结论：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翻译和应用提供了见解。
