Ferroptosis contributing to cardiomyocyte injury induced by silica nanoparticles via miR-125b-2-3p/HO-1 signaling.

IF 7.2 1区 医学 Q1 TOXICOLOGY Particle and Fibre Toxicology Pub Date : 2024-04-01 DOI:10.1186/s12989-024-00579-5
Xueyan Li, Hailin Xu, Xinying Zhao, Yan Li, Songqing Lv, Wei Zhou, Ji Wang, Zhiwei Sun, Yanbo Li, Caixia Guo
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Abstract

Background: Amorphous silica nanoparticles (SiNPs) have been gradually proven to threaten cardiac health, but pathogenesis has not been fully elucidated. Ferroptosis is a newly defined form of programmed cell death that is implicated in myocardial diseases. Nevertheless, its role in the adverse cardiac effects of SiNPs has not been described.

Results: We first reported the induction of cardiomyocyte ferroptosis by SiNPs in both in vivo and in vitro. The sub-chronic exposure to SiNPs through intratracheal instillation aroused myocardial injury, characterized by significant inflammatory infiltration and collagen hyperplasia, accompanied by elevated CK-MB and cTnT activities in serum. Meanwhile, the activation of myocardial ferroptosis by SiNPs was certified by the extensive iron overload, declined FTH1 and FTL, and lipid peroxidation. The correlation analysis among detected indexes hinted ferroptosis was responsible for the SiNPs-aroused myocardial injury. Further, in vitro tests, SiNPs triggered iron overload and lipid peroxidation in cardiomyocytes. Concomitantly, altered expressions of TfR, DMT1, FTH1, and FTL indicated dysregulated iron metabolism of cardiomyocytes upon SiNP stimuli. Also, shrinking mitochondria with ridge fracture and ruptured outer membrane were noticed. To note, the ferroptosis inhibitor Ferrostatin-1 could effectively alleviate SiNPs-induced iron overload, lipid peroxidation, and myocardial cytotoxicity. More importantly, the mechanistic investigations revealed miR-125b-2-3p-targeted HO-1 as a key player in the induction of ferroptosis by SiNPs, probably through regulating the intracellular iron metabolism to mediate iron overload and ensuing lipid peroxidation.

Conclusions: Our findings firstly underscored the fact that ferroptosis mediated by miR-125b-2-3p/HO-1 signaling was a contributor to SiNPs-induced myocardial injury, which could be of importance to elucidate the toxicity and provide new insights into the future safety applications of SiNPs-related nano products.

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纳米二氧化硅颗粒通过 miR-125b-2-3p/HO-1 信号传导导致心肌细胞损伤的铁变态反应。
背景:无定形二氧化硅纳米粒子(SiNPs)已逐渐被证明会威胁心脏健康,但其发病机制尚未完全阐明。铁凋亡是一种新定义的程序性细胞死亡形式,与心肌疾病有关。然而,它在 SiNPs 对心脏的不良影响中所起的作用尚未得到描述:结果:我们首次报道了 SiNPs 在体内和体外诱导心肌细胞铁细胞凋亡。通过气管内灌注亚慢性暴露于 SiNPs 会引起心肌损伤,表现为明显的炎症浸润和胶原增生,并伴有血清中 CK-MB 和 cTnT 活性的升高。同时,SiNPs 对心肌铁变态反应的激活表现为广泛的铁超载、FTH1 和 FTL 下降以及脂质过氧化。检测指标之间的相关性分析表明,铁变态反应是 SiNPs 引起心肌损伤的原因。此外,在体外试验中,SiNPs 引发了心肌细胞的铁超载和脂质过氧化。同时,TfR、DMT1、FTH1 和 FTL 表达的改变表明,在 SiNP 刺激下,心肌细胞的铁代谢失调。此外,还发现线粒体缩小,出现脊状断裂和外膜破裂。值得注意的是,铁氧化抑制剂 Ferrostatin-1 能有效缓解 SiNPs 诱导的铁超载、脂质过氧化和心肌细胞毒性。更重要的是,机理研究发现,miR-125b-2-3p 靶向的 HO-1 是 SiNPs 诱导铁变态反应的关键角色,可能通过调节细胞内铁代谢来介导铁超载和随之而来的脂质过氧化:我们的研究结果首次强调了由 miR-125b-2-3p/HO-1 信号传导介导的铁变态反应是 SiNPs 诱发心肌损伤的一个因素,这对于阐明 SiNPs 的毒性和为未来 SiNPs 相关纳米产品的安全应用提供新见解具有重要意义。
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来源期刊
CiteScore
15.90
自引率
4.00%
发文量
69
审稿时长
6 months
期刊介绍: Particle and Fibre Toxicology is an online journal that is open access and peer-reviewed. It covers a range of disciplines such as material science, biomaterials, and nanomedicine, focusing on the toxicological effects of particles and fibres. The journal serves as a platform for scientific debate and communication among toxicologists and scientists from different fields who work with particle and fibre materials. The main objective of the journal is to deepen our understanding of the physico-chemical properties of particles, their potential for human exposure, and the resulting biological effects. It also addresses regulatory issues related to particle exposure in workplaces and the general environment. Moreover, the journal recognizes that there are various situations where particles can pose a toxicological threat, such as the use of old materials in new applications or the introduction of new materials altogether. By encompassing all these disciplines, Particle and Fibre Toxicology provides a comprehensive source for research in this field.
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