Background. Ferroptosis plays a key role in cardiomyopathy. Atorvastatin (ATV) has a protective effect on ischemia-reperfusion (I/R) cardiomyopathy. The purpose of this study is to elucidate the mechanism of ATV in I/R injury. Methods. H9C2 cells and cardiomyopathy rats were induced by hypoxia/reoxygenation (H/R) and I/R to construct in vitro and in vivo models. Cell viability was determined by CCK8. Cardiac histopathology was observed by HE staining. Transmission electron microscope (TEM) was used to observe the mitochondrial morphology. The reactive oxygen species (ROS) content in cells was analyzed by the biochemical method. ELISA was conducted to calculate the concentrations of total iron/Fe²⁺ and hepcidin. The expression of ferroptosis and SMAD pathway-related genes were detected by qPCR. Western blot was performed to detect the expression levels of ferroptosis and SMAD pathway-related proteins. Results. In H9C2 cells, ATV reversed the decline in cell viability, mitochondrial shrinkage, and ROS elevation induced by erastin or H/R. The concentration of total iron and Fe²⁺ in H/R-induced H9C2 cells increased, and the protein expression of FPN1 decreased. After ATV treatment, the concentration of total iron and Fe²⁺ decreased, and the protein expression of FPN1 increased. The expression of the SMAD7 gene in H/R-induced H9C2 cells decreased, and the expression of the hepcidin gene increased, which were reversed by ATV. When SMAD7 was knocked down, ATV treatment failed to produce the above effect. ATV also improved ferroptosis in I/R rat myocardium through the SMAD7/hepcidin pathway. Conclusions. ATV reversed the decline in H9C2 cell viability, mitochondrial shrinkage, and ROS elevation, and improved the myocardium ferroptosis through the SMAD7/hepcidin pathway in I/R rat.

中文翻译：

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阿托伐他汀通过调控SMAD7/Hepcidin表达抑制H9C2细胞铁死亡改善缺血再灌注损伤

背景。铁死亡在心肌病中起着关键作用。阿托伐他汀 (ATV) 对缺血再灌注 (I/R) 心肌病具有保护作用。本研究的目的是阐明 ATV 在 I/R 损伤中的机制。方法。通过缺氧/复氧（H/R）和I/R诱导H9C2细胞和心肌病大鼠构建体外和体内模型。细胞活力由 CCK8 确定。HE染色观察心脏组织病理学。透射电子显微镜（TEM）用于观察线粒体形态。采用生化方法分析细胞内活性氧（ROS）含量。进行 ELISA 以计算总铁/Fe ^2+的浓度和铁调素。通过qPCR检测铁死亡和SMAD通路相关基因的表达。进行Western blot检测铁死亡和SMAD通路相关蛋白的表达水平。结果。在 H9C2 细胞中，ATV 逆转了由 erastin 或 H/R 诱导的细胞活力下降、线粒体收缩和 ROS 升高。H/R诱导的H9C2细胞总铁和Fe ²⁺浓度升高，FPN1蛋白表达降低。ATV处理后总铁和Fe ^2+浓度减少，FPN1蛋白表达增加。H/R 诱导的 H9C2 细胞中 SMAD7 基因的表达降低，铁调素基因的表达增加，这被 ATV 逆转。当 SMAD7 被击倒时，ATV 处理未能产生上述效果。ATV 还通过 SMAD7/hepcidin 通路改善了 I/R 大鼠心肌的铁死亡。结论。ATV 逆转了 H9C2 细胞活力下降、线粒体收缩和 ROS 升高，并通过 SMAD7/hepcidin 通路改善了 I/R 大鼠的心肌铁死亡。