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Published on: May 16, 2020
Downregulating miR-432-5p exacerbates adriamycin-induced cardiotoxicity via activating the RTN3 signaling pathway
Wei Geng1, Shaohua Yan1, Dasen Sang1
1Department of Cardiology, Baoding No.1 Central Hospital, Baoding, Hebei Province, China.
Background:
Adriamycin (ADR) is a widely used chemotherapy drug in clinical practice and it causes toxicity in the myocardium affecting its clinical use. miR-432-5p is a miRNA primarily expressed in myocardial cells and has a protective effect in the myocardium. We aim to explore the protective effect of miR-432-5p on ADR-caused impaired mitochondrial ATP metabolism and endoplasmic reticulum stress (ERs).
Method:
The primary cardiomyocytes were obtained from neonatal mice and the ADR was added to cells, meanwhile, a mice model was constructed through intravenous ADR challenge, and expression levels of miR-432-5p were examined. Subsequently, the miR-432-5p was introduced in vitro and in vivo to explore its effect on the activity of mitochondrial ATP synthesis, autophagy, and ER stress. The bioinformatics analysis was performed to explore the target of miR-432-5p.
Results:
ADR decreased the expression of miR-432-5p in cardiomyocytes. It also decreases mitochondrial ATP production and activates the ER stress pathway by increasing the expression of LC3B, Beclin 1, cleaved caspase 3, and induces cardiac toxicity. miR-432-5p exogenous supplementation can reduce the cardiotoxicity caused by ADR, and its protective effect on cardiomyocytes depends on the down-regulation of the RTN3 signaling pathway in ER.
Conclusion:
ADR can induce the low expression of miR-432-5p, and activate the RTN3 pathway in ER, increase the expression of LC3B, Beclin 1, cleaved caspase 3, CHOP, and RTN3, and induce cardiac toxicity.
Insights
Adriamycin (ADR) chemotherapy causes cardiotoxicity by reducing miR-432-5p and impairing mitochondrial function. Restoring miR-432-5p protects the heart by down-regulating ER stress and the RTN3 pathway.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Adriamycin (ADR) is a crucial chemotherapy agent with known cardiotoxicity.
- Myocardial cells express miR-432-5p, which exhibits protective properties.
- ADR-induced cardiotoxicity involves impaired mitochondrial ATP metabolism and endoplasmic reticulum stress (ERs).
Purpose of the Study:
- To investigate the protective role of miR-432-5p against ADR-induced cardiotoxicity.
- To elucidate the effects of miR-432-5p on mitochondrial ATP metabolism and ER stress in cardiomyocytes.
Main Methods:
- Primary cardiomyocytes and a mouse model were used to assess ADR effects and miR-432-5p levels.
- miR-432-5p was introduced in vitro and in vivo to evaluate its impact on ATP synthesis, autophagy, and ER stress.
- Bioinformatics analysis identified miR-432-5p targets.
Main Results:
- ADR treatment reduced miR-432-5p expression in cardiomyocytes.
- ADR decreased mitochondrial ATP production and activated ER stress, indicated by increased LC3B, Beclin 1, and cleaved caspase 3.
- Exogenous miR-432-5p supplementation mitigated ADR-induced cardiotoxicity by down-regulating the ER-associated RTN3 signaling pathway.
Conclusions:
- ADR induces cardiotoxicity through decreased miR-432-5p expression and activation of the ER RTN3 pathway.
- This activation leads to increased expression of LC3B, Beclin 1, cleaved caspase 3, CHOP, and RTN3.
- miR-432-5p plays a critical role in protecting cardiomyocytes against ADR-induced damage.
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