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Updated: Jun 13, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
ELABELA-32 Alleviates Doxorubicin-Induced Chronic Cardiotoxicity by Inhibiting the TGF-β/Smad Signaling Pathway
Shuang Zhou1, Zhuo Meng2, Lin Lu1
1Department of Intensive Care Unit, Xiamen Cardiovascular Hospital, Xiamen University, No. 2999, Jinshan Road, Huli District, Xiamen, Fujian, China.
Insights
ELABELA (ELA)-32 peptide protects against doxorubicin-induced heart damage by reducing oxidative stress and fibrosis. This peptide therapy shows potential for preventing chemotherapy-related cardiotoxicity.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Doxorubicin (DOX) chemotherapy can cause significant cardiotoxicity, characterized by cardiac fibrosis, oxidative stress, and cardiomyocyte apoptosis.
- ELABELA (ELA), an endogenous ligand for the apelin receptor (APJ/APLNR), plays a role in cardiovascular regulation.
- The specific protective mechanisms of ELA-32 against DOX-induced cardiotoxicity require further elucidation.
Purpose of the Study:
- To investigate the cardioprotective effects of ELA-32 against doxorubicin-induced cardiotoxicity.
- To elucidate the underlying molecular mechanisms, particularly the involvement of the TGF-β/Smad signaling pathway.
Main Methods:
- A mouse model of chronic doxorubicin cardiotoxicity was established (20 mg/kg cumulative dose).
- Exogenous ELA-32 was administered via microinjection pump to assess its effects on cardiac function, oxidative stress, and fibrosis.
- In vitro studies utilized rat cardiomyocytes (H9C2 cells) to evaluate ELA-32's protection against DOX-induced cytotoxicity.
- The role of the TGF-β/Smad pathway was assessed by activating it with TGF-β1.
Main Results:
- ELA-32 administration significantly improved cardiac function and survival in mice subjected to chronic DOX treatment.
- Exogenous ELA-32 reduced oxidative stress markers and myocardial fibrosis in the DOX-induced cardiotoxicity model.
- In vitro, ELA-32 pretreatment protected H9C2 cells from DOX-induced cytotoxicity.
- The cardioprotective effects of ELA-32 were abolished upon activation of the TGF-β/Smad signaling pathway.
Conclusions:
- ELA-32 demonstrates significant cardioprotective effects against chronic doxorubicin-induced cardiotoxicity.
- The mechanism involves the modulation of the TGF-β/Smad signaling pathway, attenuating cardiac fibrosis.
- ELA-32 holds promise as a therapeutic agent for preventing or treating doxorubicin-related cardiotoxicity.
Abstract:
Cardiac fibrosis, oxidative stress, and cardiomyocyte apoptosis are key contributors to the progression of doxorubicin (DOX)-induced cardiotoxicity. ELABELA (ELA) is an early endogenous ligand of apelin receptor (APJ/APLNR), which is a G protein-coupled receptor with seven transmembrane domains. Our present study aimed to investigate the protective role and underlying mechanism of ELA-32 in mitigating oxidative stress and fibrosis associated with DOX-induced cardiotoxicity. Using a mouse model of chronic DOX cardiotoxicity (5 mg/kg, i.p, once a week for four times, the total cumulative dose is 20 mg/kg), it was found that exogenous administration of ELA-32 using a microinjection pump significantly improved cardiac function, reduced oxidative stress, and myocardial fibrosis, and enhanced survival. Furthermore, pretreatment with ELA-32 peptide protected rat cardiomyocytes (H9C2 cells) from DOX-induced cytotoxicity in vitro. However, these cardioprotective effects of ELA-32 were no longer observed after activation of the Smad signaling pathway using TGF-β1. In summary, ELA-32 attenuated DOX-induced cardiac fibrosis through by modulating the TGF-β/Smad signaling pathway, thus highlighting its potential as a therapeutic agent for preventing chronic DOX-related cardiotoxicity.
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