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Loss of circular EYA3 attenuates formaldehyde-induced cardiomyocyte pyroptosis and congenital heart defects by regulating Smad5 stability

IF 8.2 1区环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES

Science of the Total Environment Pub Date : 2025-05-27 DOI:10.1016/j.scitotenv.2025.179752

Ying Zhang , Yanyan Yang , Xiangqin He , Pin Sun , Xiaoxia Song , Yu Tian , Jianmin Ma , Ruicong Sun , Tao Yu , Zhirong Jiang

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引用次数: 0

Abstract

Formaldehyde (FA) is a significant risk factor that impacts fetal heart development. Circular RNAs (circRNAs) have been recognized as potent regulators of heart development and disease. We discovered a particular circRNA, circEYA3 (rno_circ_009926), which is upregulated in cardiomyocytes and fetal rat heart tissue exposed to FA. Additionally, circEYA3 shows elevated expression in the serum of pregnant women who have been exposed to FA and whose fetuses have congenital heart disease (CHD). While circEYA3 knockdown inhibited FA-induced cardiomyocyte pyroptosis, circEYA3 overexpression exhibited the opposite effect. Our results showed that circEYA3 interacts with SMAD family member 5 (Smad5) protein, serving as a scaffold to enhance the association between Smad5 and the Smad5 ubiquitination regulatory factor 1 (Smurf1). CircEYA3 knockdown stabilised Smad5 at the post-translational level by upregulating Smad5 and promoting Smurf1-mediated Smad5 ubiquitination. In addition, we found that circEYA3 knockdown in an FA-exposed foetal rat heart model inhibited foetal rat cardiomyocyte pyroptosis and ameliorated abnormal heart development in vivo. Overall, our work links circEYA3 to the onset of fetal CHDs induced by maternal FA exposure and provides potential therapeutic and diagnostic strategies targeting circEYA3 for CHDs.

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圆形EYA3的缺失通过调节Smad5的稳定性来减弱甲醛诱导的心肌细胞焦亡和先天性心脏缺陷

甲醛（FA）是影响胎儿心脏发育的重要危险因素。环状rna （circRNAs）已被认为是心脏发育和疾病的有效调节因子。我们发现了一种特殊的circRNA circEYA3 (rno_circ_009926)，它在暴露于FA的心肌细胞和胎鼠心脏组织中上调。此外，circEYA3在暴露于FA和胎儿患有先天性心脏病（CHD）的孕妇血清中表达升高。circEYA3敲低抑制fa诱导的心肌细胞焦亡，而circEYA3过表达则表现出相反的效果。我们的研究结果表明，circEYA3与SMAD家族成员5 （Smad5）蛋白相互作用，作为支架增强Smad5与Smad5泛素化调节因子1 （Smurf1）之间的关联。CircEYA3敲低通过上调Smad5和促进smurf1介导的Smad5泛素化，在翻译后水平稳定Smad5。此外，我们发现在暴露于fa的胎鼠心脏模型中，circEYA3敲低可抑制胎鼠心肌细胞焦亡，并改善体内心脏异常发育。总的来说，我们的工作将circEYA3与母体FA暴露诱导的胎儿冠心病的发病联系起来，并提供了针对circEYA3治疗冠心病的潜在治疗和诊断策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science of the Total Environment

Science of the Total Environment 环境科学-环境科学

CiteScore

17.60

自引率

10.20%

发文量

8726

审稿时长

2.4 months

期刊介绍： The Science of the Total Environment is an international journal dedicated to scientific research on the environment and its interaction with humanity. It covers a wide range of disciplines and seeks to publish innovative, hypothesis-driven, and impactful research that explores the entire environment, including the atmosphere, lithosphere, hydrosphere, biosphere, and anthroposphere. The journal's updated Aims & Scope emphasizes the importance of interdisciplinary environmental research with broad impact. Priority is given to studies that advance fundamental understanding and explore the interconnectedness of multiple environmental spheres. Field studies are preferred, while laboratory experiments must demonstrate significant methodological advancements or mechanistic insights with direct relevance to the environment.

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