Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis
Loss of Cardiac Ferritin H Facilitates Cardiomyopathy via Slc7a11-Mediated Ferroptosis
复制标题
心肌铁蛋白 H 缺失通过 Slc7a11 介导的铁死亡促进心肌病
DOI：
10.1161/circresaha.120.316509
复制
发表时间：
2020-07-31
影响因子：
20.1
通讯作者：
Wang, Fudi
中科院分区：
文献类型：
--
作者：
Fang, Xuexian;Cai, Zhaoxian;Wang, Fudi
补充数字内容可在正文中找到。理论基础：维持铁稳态对于正常的心脏功能是必不可少的。缺铁和铁负荷过多都通过复杂的机制与心肌病和心力衰竭相关。尽管铁蛋白通过储存过量的细胞铁在铁代谢中发挥核心作用，但在心肌细胞中铁蛋白的分子功能仍不清楚。目的：探讨FTH(铁蛋白H)在调节心脏铁稳态和心脏病中的作用。方法和结果：将表达条件FTH基因敲除等位基因的小鼠与两个不同的表达Cre重组酶的小鼠品系杂交，产生在心肌细胞(MCK-Cre)或心肌细胞(MYH6-Cre)中缺乏FTH特异性表达的后代。心肌细胞中FTH缺乏的小鼠心脏铁水平降低，氧化应激增加，导致衰老后轻微的心脏损伤。然而，以高铁饮食喂养这些小鼠会导致严重的心脏损伤和肥厚性心肌病，具有典型的铁下垂的分子特征，包括谷胱甘肽(GSH)水平降低和脂质过氧化增加。铁性下垂的特异性抑制剂铁抑素-1挽救了这一表型，支持了铁性下垂在心脏中起到病理生理作用的观点。最后，我们发现FTH缺乏的心肌细胞减少了铁性下垂调节剂SLc7a11的表达，而在心肌细胞中选择性地过度表达SLc7a11提高了GSH水平，预防了心脏铁下垂。结论：我们的发现提供了令人信服的证据，表明铁蛋白在预防心脏铁下垂和随后的心力衰竭方面发挥着重要作用，从而为有发展为心肌病风险的患者提供了一个可能的新的治疗靶点。
Supplemental Digital Content is available in the text. Rationale: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. Objective: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. Methods and Results: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. Conclusions: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.