Research Paper Volume 16, Issue 7 pp 5916—5928
Downregulating miRNA-199a-5p exacerbates fluorouracil-induced cardiotoxicity by activating the ATF6 signaling pathway
- 1 Department of Oncology, The First Hospital of Hebei Medical University, Yuhua, Shijiazhuang 050031 Hebei, China
- 2 Department of Cardiology, The First Hospital of Hebei Medical University, Yuhua, Shijiazhuang 050031, Hebei, China
- 3 Hebei Key Laboratory of Heart and Metabolism, Shijiazhuang 050031, Hebei, China
Received: October 25, 2023 Accepted: February 27, 2024 Published: March 25, 2024
https://doi.org/10.18632/aging.205679How to Cite
Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 in vitro. The expression of miRNA-199a-5p and its regulation were explored in vitro and in vivo.
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.