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Updated: Jun 10, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Neuregulin-1 reduces Doxorubicin-induced cardiotoxicity by upregulating YAP to inhibit senescence
Henghe Shi1, Yifei Zou1, Yinghao Li1
1Department of Cardiology, The Second Hospital of Jilin University, No. 4026 Yatai Street, Changchun, Jilin Province 130041, China.
Abstract:
The cardiotoxicity of Doxorubicin (Dox) limits its clinical application, creating an urgent need to investigate its underlying mechanism and develop effective therapies. Senescence plays an important role in Dox-induced cardiotoxicity (DIC). Recently, Neuregulin-1 (NRG1) was found to regulate Yes-associated protein (YAP), which was reported to inhibit senescence, suggesting that NRG1 might be used to treat DIC by inhibiting senescence through YAP regulation. We examined the changes and regulatory roles of YAP and senescence in Dox cardiotoxicity and whether NRG1 could reduce DIC in chronic DIC mice and Dox-treated H9c2 cells. Our study revealed that sustained small doses of Dox impaired cardiac function and H9c2 cell viability, induced myocardial senescence, and inhibited YAP expression. Conversely, high levels of YAP inhibited Dox-induced senescence in H9c2 cells, indicating that Dox promotes myocardial senescence by inhibiting YAP. In addition, we found that exogenous NRG1 inhibited the phosphorylation of LATS1 and MST1, thereby inhibiting YAP phosphorylation and promote the nuclear translocation of YAP, inhibiting senescence and attenuating Dox-induced cardiotoxicity. YAP knockdown or inhibition of YAP binding to TEA domain transcription factor protein （TEAD）blocks the protective effects of NRG1. In conclusion, our study suggests that Dox-induced myocardial senescence through YAP inhibition is one of the pathological mechanisms of its cardiotoxicity. Additionally, NRG1 reduces DIC by upregulating YAP to inhibit senescence.
Insights
Doxorubicin (Dox) causes heart damage by promoting cell senescence via YAP inhibition. Neuregulin-1 (NRG1) protects the heart by upregulating YAP, reducing senescence and Dox-induced cardiotoxicity.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Doxorubicin (Dox) cardiotoxicity is a major clinical limitation.
- Cellular senescence is a key mechanism in Dox-induced cardiotoxicity (DIC).
- Neuregulin-1 (NRG1) may offer a therapeutic strategy by modulating senescence via Yes-associated protein (YAP).
Purpose of the Study:
- To investigate the roles of YAP and senescence in Dox cardiotoxicity.
- To determine if NRG1 can mitigate DIC.
- To elucidate the molecular mechanisms underlying NRG1's protective effects.
Main Methods:
- Utilized chronic DIC mouse models and Dox-treated H9c2 cells.
- Assessed cardiac function, cell viability, senescence markers, and YAP expression.
- Investigated the effects of exogenous NRG1 on YAP signaling pathways (LATS1, MST1 phosphorylation).
- Examined the impact of YAP knockdown and YAP-TEAD inhibition on NRG1's protective effects.
Main Results:
- Sustained low-dose Dox impaired cardiac function, reduced cell viability, induced myocardial senescence, and inhibited YAP expression.
- High YAP levels suppressed Dox-induced senescence in H9c2 cells.
- NRG1 inhibited LATS1/MST1 phosphorylation, promoting YAP nuclear translocation, thereby inhibiting senescence and reducing DIC.
- YAP knockdown or YAP-TEAD pathway inhibition abolished NRG1's cardioprotective effects.
Conclusions:
- Dox-induced cardiotoxicity involves myocardial senescence mediated by YAP inhibition.
- NRG1 exerts cardioprotective effects against Dox by upregulating YAP and inhibiting senescence.
- Targeting the NRG1-YAP pathway presents a potential therapeutic approach for DIC.
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