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Updated: Feb 28, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with
Yan Xia1, Zhangwei Chen1, Ao Chen1
1Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China.
Aims:
LCZ696, a novel angiotensin receptor neprilysin inhibitor, is effective in treating heart failure patients. Doxorubicin (DOX) is an effective antitumor medication but the cardiotoxicity limited its clinical use. In this study, we aimed to determine the effect of LCZ696 on DOX-induced cardiomyopathy in mice and in vitro and to explore related mechanisms focusing on fission protein dynamin-related protein 1 (Drp1).
Methods And Results:
In human study, we found that myocardial fission protein Drp1 expression and its ser 616 phosphorylation were significantly increased in dilated cardiomyopathy (DCM) patients. Male Balb/c mice and H9c2 cardiomyocytes were randomized into three groups: saline, DOX, DOX plus LCZ696. Reduced cardiac function, mitochondrial morphology disturbance, reduced activity of mitochondrial respiration complex I and lowered adenosine triphosphate (ATP) content were detected post DOX stimulation in mice, which could be significantly improved by LCZ696. Fission protein Drp1 and its ser 616 phosphorylation were also increased post DOX and which could be reduced by LCZ696. In vitro, increased cardiomyocyte apoptosis, Drp1 ser 616 phosphorylation post DOX stimulation could be significantly attenuated by LCZ696 or Drp1 specific inhibitor Midivi-1. Furthermore, over-expression of Drp1 abrogated the protection effect of LCZ696 against DOX-induced cardiotoxicity in H9c2 cells.
Conclusion:
The protective effect of LCZ696 against DOX-induced cardiac dysfunction is at least partly associated with alleviating Drp1-mediated mitochondrial dysfunction.
Insights
LCZ696 protects against doxorubicin-induced heart damage by reducing fission protein dynamin-related protein 1 (Drp1) activity and improving mitochondrial function in mice and cells.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Mitochondrial Biology
Background:
- Doxorubicin (DOX) is an effective anticancer drug but its clinical use is limited by cardiotoxicity.
- LCZ696 is a novel angiotensin receptor neprilysin inhibitor used for heart failure.
- Increased dynamin-related protein 1 (Drp1) activity is implicated in heart disease.
Purpose of the Study:
- To investigate the protective effect of LCZ696 against doxorubicin-induced cardiomyopathy.
- To explore the role of Drp1 in doxorubicin-induced cardiotoxicity and LCZ696's mechanism of action.
Main Methods:
- Studies were conducted in mice and H9c2 cardiomyocytes.
- Animals and cells were treated with saline, doxorubicin (DOX), or DOX plus LCZ696.
- Key markers of cardiac function, mitochondrial health, and Drp1 activity were assessed.
Main Results:
- DOX induced cardiac dysfunction, mitochondrial damage, and increased Drp1 activity and phosphorylation.
- LCZ696 treatment significantly improved cardiac function and mitochondrial parameters in DOX-treated subjects.
- LCZ696 reduced Drp1 activity and phosphorylation, and its protective effects were diminished by Drp1 overexpression.
Conclusions:
- LCZ696 demonstrates a protective effect against doxorubicin-induced cardiotoxicity.
- This protection is partly mediated by the alleviation of Drp1-related mitochondrial dysfunction.
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