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Downregulating miRNA-199a-5p exacerbates fluorouracil-induced cardiotoxicity by activating the ATF6 signaling pathway.
- Source :
-
Aging [Aging (Albany NY)] 2024 Mar 25; Vol. 16 (7), pp. 5916-5928. Date of Electronic Publication: 2024 Mar 25. - Publication Year :
- 2024
-
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.<br />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 .<br />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.<br />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.
- Subjects :
- Animals
Rats
Cells, Cultured
Rats, Sprague-Dawley
Male
Activating Transcription Factor 6 metabolism
Activating Transcription Factor 6 genetics
MicroRNAs metabolism
MicroRNAs genetics
Myocytes, Cardiac drug effects
Myocytes, Cardiac metabolism
Signal Transduction drug effects
Down-Regulation drug effects
Fluorouracil toxicity
Fluorouracil adverse effects
Cardiotoxicity metabolism
Cardiotoxicity genetics
Cardiotoxicity etiology
Endoplasmic Reticulum Stress drug effects
Endoplasmic Reticulum Chaperone BiP
Subjects
Details
- Language :
- English
- ISSN :
- 1945-4589
- Volume :
- 16
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Aging
- Publication Type :
- Academic Journal
- Accession number :
- 38536006
- Full Text :
- https://doi.org/10.18632/aging.205679