Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China.
J Zhejiang Univ Sci B. 2024 May 15;25(5):422-437. doi: 10.1631/jzus.B2300077.
Viral myocarditis (VMC) is one of the most common acquired heart diseases in children and teenagers. However, its pathogenesis is still unclear, and effective treatments are lacking. This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes (CMCs) induced by coxsackievirus B3 (CVB3). CVB3 was utilized for inducing the VMC mouse model and cellular model. Cardiac echocardiography, left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were implemented to assess the cardiac function. In CVB3-induced VMC mice, cardiac insufficiency was observed, as well as the altered levels of ferroptosis-related indicators (glutathione peroxidase 4 (GPX4), glutathione (GSH), and malondialdehyde (MDA)). However, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) could restore the changes caused by CVB3 stimulation. was enriched in hucMSCs-exo, and the inhibitory effect of hucMSCs-exo on CVB3-induced ferroptosis was higher than that of hucMSCs-exo (NC: negative control). Mothers against decapentaplegic homolog 2 (SMAD2) increased in the VMC group, while the expression of zinc-finger protein 36 (ZFP36) decreased. was confirmed to interact with messenger RNA (mRNA), and the SMAD2 protein interacted directly with the ZFP36 protein. Silencing and overexpressing inhibited the expression of ferroptosis-related indicators. Meanwhile, the levels of GPX4, solute carrier family 7, member 11 (SLC7A11), and GSH were lower in the overexpression plasmid (oe-)+ mimic group than in the oe-NC+ mimic group, while those of MDA, reactive oxygen species (ROS), and Fe increased. In conclusion, these data showed that ferroptosis could be regulated by mediating expression. Exo- derived from hucMSCs could mediate to promote the expression of ZFP36, which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.
病毒性心肌炎 (VMC) 是儿童和青少年最常见的获得性心脏病之一。然而，其发病机制尚不清楚，且缺乏有效的治疗方法。本研究旨在探讨外泌体通过何种调控途径减轻柯萨奇病毒 B3 (CVB3) 诱导的心肌细胞 (CMCs) 铁死亡。利用 CVB3 诱导 VMC 小鼠模型和细胞模型。实施心脏超声心动图、左心室射血分数 (LVEF) 和左心室缩短分数 (LVFS) 评估心功能。在 CVB3 诱导的 VMC 小鼠中，观察到心功能不全以及铁死亡相关指标 (谷胱甘肽过氧化物酶 4 (GPX4)、谷胱甘肽 (GSH) 和丙二醛 (MDA)) 的改变。然而，人脐带间充质干细胞来源的外泌体 (hucMSCs-exo) 可恢复 CVB3 刺激引起的变化。 在 hucMSCs-exo 中富集，hucMSCs-exo 对 CVB3 诱导的铁死亡的抑制作用高于 hucMSCs-exo (NC：阴性对照)。SMAD2 在 VMC 组中增加，而锌指蛋白 36 (ZFP36) 的表达减少。 被证实与 信使 RNA (mRNA) 相互作用，SMAD2 蛋白与 ZFP36 蛋白直接相互作用。沉默 和过表达 抑制铁死亡相关指标的表达。同时，过表达质粒 (oe-)+ 模拟物组的 GPX4、溶质载体家族 7 成员 11 (SLC7A11) 和 GSH 水平低于 oe-NC+ 模拟物组，而 MDA、活性氧 (ROS) 和 Fe 水平升高。总之，这些数据表明铁死亡可通过调节 表达进行调节。来自 hucMSCs 的 Exo- 可以调节 以促进 ZFP36 的表达，进而抑制 CMCs 的铁死亡，从而缓解 CVB3 诱导的 VMC。
