背景:尽管心肌梗死(MI)治疗后血流恢复,心肌缺血再灌注(I/R)可引起心脏损伤,这是心力衰竭的主要原因。天麻素(GAS)对大脑具有保护作用,心,和肾脏I/R然而,其在心肌I/R损伤(MIRI)中的药理机制尚不清楚。
目的:GAS调节多种疾病的自噬,比如急性肝炎,血管性痴呆,和中风。我们假设GAS可以修复线粒体损伤并调节自噬以防止MIRI。
方法:雄性C57BL/6小鼠和H9C2细胞在GAS给药后进行I/R和缺氧-复氧(H/R)损伤,分别,为了评估GAS对心肌细胞表型的影响,心,线粒体结构和功能。临床上已观察到GAS对心脏手术患者心功能和线粒体结构的影响。
方法:GAS对心脏结构和功能的影响,线粒体结构,和相关分子在MIRI动物模型中的表达使用免疫组织化学染色进行评估,酶联免疫吸附测定(ELISA),透射电子显微镜,西方印迹,和基因测序。它对形态学的影响,分子,和功能表型的心肌细胞进行H/R使用免疫组织化学染色观察,实时定量PCR,和西方印迹。
结果:GAS在动物模型中显著减少MIRI小鼠的心肌梗死面积和改善心脏功能,在细胞模型中增加心肌细胞活力和减少心肌细胞损伤。在临床实践中,心脏手术患者应用GAS后,心肌损伤减轻,心功能改善;线粒体和自噬激活也得到了改善。GAS主要通过激活PINK1/Parkin通路发挥心脏保护作用,促进线粒体自噬清除受损的线粒体。
结论:GAS可以通过PINK1/Parkin促进线粒体自噬和保护线粒体,因此表明其作为有效的围手术期心肌保护剂的巨大潜力。
BACKGROUND: Although blood flow is restored after treatment of myocardial infarction (MI), myocardial ischemia and reperfusion (I/R) can cause cardiac injury, which is a leading cause of heart failure.
Gastrodin (GAS) exerts protective effects against brain, heart, and kidney I/R. However, its pharmacological mechanism in myocardial I/R injury (MIRI) remains unclear.
OBJECTIVE: GAS regulates autophagy in various diseases, such as acute hepatitis, vascular dementia, and stroke. We hypothesized that GAS could repair mitochondrial damage and regulate autophagy to protect against MIRI.
METHODS: Male C57BL/6 mice and H9C2 cells were subjected to I/R and hypoxia-reoxygenation (H/R) injury after GAS administration, respectively, to assess the impact of GAS on cardiomyocyte phenotypes, heart, and mitochondrial structure and function. The effect of GAS on cardiac function and mitochondrial structure in patients undergoing cardiac surgery has been observed in clinical practice.
METHODS: The effects of GAS on cardiac structure and function, mitochondrial structure, and expression of related molecules in an animal model of MIRI were evaluated using immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy, western blotting, and gene sequencing. Its effects on the morphological, molecular, and functional phenotypes of cardiomyocytes undergoing H/R were observed using immunohistochemical staining, real-time quantitative PCR, and western blotting.
RESULTS: GAS significantly reduces myocardial infarct size and improves cardiac function in MIRI mice in animal models and increases cardiomyocyte viability and reduces cardiomyocyte damage in cellular models. In clinical practice, myocardial injury was alleviated with better cardiac function in patients undergoing cardiac surgery after the application of GAS; improvements in mitochondria and autophagy activation were also observed. GAS primarily exerts cardioprotective effects through activation of the PINK1/Parkin pathway, which promotes mitochondrial autophagy to clear damaged mitochondria.
CONCLUSIONS: GAS can promote mitophagy and preserve mitochondria through PINK1/Parkin, thus indicating its tremendous potential as an effective perioperative myocardial protective agent.