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下调miRNA-199a-5p通过激活ATF6信号通路加重氟尿嘧啶诱导的心脏毒性。

Downregulating miRNA-199a-5p exacerbates fluorouracil-induced cardiotoxicity by activating the ATF6 signaling pathway.

作者信息

Wang Wei, Dong Liang, Lv Hengxu, An Yonghui, Zhang Changwang, Zheng Zheng, Guo Ying, He Li, Wang Libin, Wang Jinmei, Shi Xinlei, Li Na, Zheng Mingqi

机构信息

Department of Oncology, The First Hospital of Hebei Medical University, Yuhua, Shijiazhuang 050031 Hebei, China.

Department of Cardiology, The First Hospital of Hebei Medical University, Yuhua, Shijiazhuang 050031, Hebei, China.

出版信息

Aging (Albany NY). 2024 Mar 25;16(7):5916-5928. doi: 10.18632/aging.205679.

DOI:10.18632/aging.205679
PMID:38536006
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11042954/
Abstract

BACKGROUND

Fluorouracil (5-FU) might produce serious cardiac toxic reactions. miRNA-199a-5p is a miRNA primarily expressed in myocardial cells and has a protective effect on vascular endothelium. Under hypoxia stress, the expression level of miRNA-199a-5p was significantly downregulated and is closely related to cardiovascular events such as coronary heart disease, heart failure, and hypertension. We explored whether 5-FU activates the endoplasmic reticulum stress ATF6 pathway by regulating the expression of miRNA-199a-5p in cardiac toxicity.

METHODS

This project established a model of primary cardiomyocytes derived from neonatal rats and treated them with 5-FU . The expression of miRNA-199a-5p and its regulation were explored and .

RESULTS

5-FU decreases the expression of miRNA-199a-5p in cardiomyocytes, activates the endoplasmic reticulum stress ATF6 pathway, and increases the expression of GRP78 and ATF6, affecting the function of cardiomyocytes, and induces cardiac toxicity. The rescue assay further confirmed that miRNA-199a-5p supplementation can reduce the cardiotoxicity caused by 5-FU, and its protective effect on cardiomyocytes depends on the downregulation of the endoplasmic reticulum ATF6 signaling pathway.

CONCLUSIONS

5-FU can down-regulate expression of miRNA-199a-5p, then activate the endoplasmic reticulum stress ATF6 pathway, increase the expression of GRP78 and ATF6, affect the function of cardiomyocytes, and induce cardiac toxicity.

摘要

背景

氟尿嘧啶（5-FU）可能会产生严重的心脏毒性反应。miRNA-199a-5p是一种主要在心肌细胞中表达的微小RNA，对血管内皮具有保护作用。在缺氧应激下，miRNA-199a-5p的表达水平显著下调，且与冠心病、心力衰竭和高血压等心血管事件密切相关。我们探讨了5-FU在心脏毒性中是否通过调节miRNA-199a-5p的表达来激活内质网应激ATF6通路。

方法

本项目建立了新生大鼠原代心肌细胞模型并用5-FU进行处理。探讨了miRNA-199a-5p的表达及其调控情况。

结果

5-FU降低心肌细胞中miRNA-199a-5p的表达，激活内质网应激ATF6通路，增加GRP78和ATF6的表达，影响心肌细胞功能，并诱导心脏毒性。挽救实验进一步证实，补充miRNA-199a-5p可降低5-FU所致的心脏毒性，其对心肌细胞的保护作用依赖于内质网ATF6信号通路的下调。

结论

5-FU可下调miRNA-199a-5p的表达，进而激活内质网应激ATF6通路，增加GRP78和ATF6的表达，影响心肌细胞功能，并诱导心脏毒性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/68dd10940f3a/aging-16-205679-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/682d06c53246/aging-16-205679-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/baab7dcc8cb7/aging-16-205679-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/adb8e5cc9a04/aging-16-205679-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/038a6844d746/aging-16-205679-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/b32962e1cf17/aging-16-205679-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/d964d0d669bb/aging-16-205679-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/68dd10940f3a/aging-16-205679-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/682d06c53246/aging-16-205679-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/baab7dcc8cb7/aging-16-205679-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/adb8e5cc9a04/aging-16-205679-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/038a6844d746/aging-16-205679-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/b32962e1cf17/aging-16-205679-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/d964d0d669bb/aging-16-205679-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0667/11042954/68dd10940f3a/aging-16-205679-g007.jpg

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