Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany.
Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany; Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany.
J Mol Cell Cardiol. 2024 Nov;196:125-140. doi: 10.1016/j.yjmcc.2024.09.012. Epub 2024 Sep 26.
Heart failure (HF) is a burgeoning health problem worldwide. Often arising as a result of cardiac injury, HF has become a major cause of mortality with limited availability of effective treatments. Ferroptotic pathways, triggering an iron-dependent form of cell death, are known to be potential key players in heart disease. This form of cell death does not exhibit typical characteristics of programmed cell death, and is mediated by impaired iron metabolism and lipid peroxidation signalling.
The aim of this study is to establish an ex-vivo model of myocardial injury in living myocardial slices (LMS) and to identify novel underlying mechanisms and potential therapeutic druggable target(s).
In this study, we employed LMS as an ex vivo model of cardiac injury to investigate underlying mechanisms and potential therapeutic targets. Cryoinjury was induced in adult rat LMS, resulting in 30 % tissue damage. Cryoinjured LMS demonstrated impaired contractile function, cardiomyocyte hypertrophy, inflammation, and cardiac fibrosis, closely resembling in vivo cardiac injury characteristics. Proteomic analysis revealed an enrichment of factors associated with ferroptosis in the injured LMS, suggesting a potential causative role. To test this hypothesis, we pharmacologically inhibited ferroptotic pathways using ferrostatin (Fer-1) in the cryoinjured rat LMS, resulting in attenuation of structural changes and repression of pro-fibrotic processes. Furthermore, LMS generated from failing human hearts were used as a model of chronic heart failure. In this model, Fer-1 treatment was observed to reduce the expression of ferroptotic genes, enhances contractile function and improves tissue viability. Blocking ferroptosis-associated pathways in human cardiac fibroblasts (HCFs) resulted in a downregulation of fibroblast activation genes, a decrease in fibroblast migration capacity, and a reduction in reactive oxygen species production. RNA sequencing analysis of Fer-1-treated human LMS implicated metallothioneins as a potential underlying mechanism for the inhibition of these pathways. This effect is possibly mediated through the replenishment of glutathione reserves.
Our findings highlight the potential of targeting ferroptosis-related pathways and metallothioneins as a promising strategy for the treatment of heart disease.
心力衰竭（HF）是全球日益严重的健康问题。HF 通常是由于心脏损伤引起的，由于有效治疗方法的有限可用性，它已成为主要的死亡原因。铁死亡途径，引发一种依赖铁的细胞死亡形式，已知是心脏病的潜在关键因素。这种形式的细胞死亡不表现出典型的程序性细胞死亡特征，并且由铁代谢和脂质过氧化信号传导受损介导。
本研究旨在建立活心肌切片（LMS）心肌损伤的体外模型，并确定潜在的潜在机制和潜在的治疗药物靶点。
在这项研究中，我们使用 LMS 作为心脏损伤的体外模型来研究潜在机制和潜在治疗靶点。在成年大鼠 LMS 中诱导冷冻损伤，导致 30%的组织损伤。冷冻损伤的 LMS 表现出收缩功能受损、心肌细胞肥大、炎症和心脏纤维化，与体内心脏损伤特征非常相似。蛋白质组学分析显示，损伤的 LMS 中与铁死亡相关的因素丰富，提示其潜在的致病作用。为了验证这一假设，我们在冷冻损伤的大鼠 LMS 中使用铁死亡抑制剂（Fer-1）抑制铁死亡途径，结果表明结构变化减弱，促纤维化过程受到抑制。此外，我们还使用来自心力衰竭患者的 LMS 作为慢性心力衰竭的模型。在该模型中，观察到 Fer-1 治疗可降低铁死亡基因的表达，增强收缩功能并提高组织活力。在人心脏成纤维细胞（HCFs）中阻断铁死亡相关途径可导致成纤维细胞激活基因下调、成纤维细胞迁移能力降低以及活性氧生成减少。Fer-1 处理的人 LMS 的 RNA 测序分析表明，金属硫蛋白可能是抑制这些途径的潜在机制。这种作用可能是通过补充谷胱甘肽储备来介导的。
我们的研究结果强调了靶向铁死亡相关途径和金属硫蛋白作为治疗心脏病的有前途策略的潜力。
