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Updated: Dec 30, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
MiR-526b-3p mediates doxorubicin-induced cardiotoxicity by targeting STAT3 to inactivate VEGFA
Lifu Zhang1, Liyan Liu2, Xun Li3
1Department of Cardiovascular Medicine, the First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China; Electrocardiogram Room, Jiangxi Cancer Hospital, Nanchang, 330029, Jiangxi, China.
Abstract:
Doxorubicin (DOX), a wide-spectrum chemotherapeutic agent, is recognized to have cardiotoxic side effects when it is applied in hematological diseases and solid tumor management. However, the mechanisms behind the DOX-induced anomaly of vascular homeostasis remain mostly elusive. qRT-PCR and immumohistochemical staining indicated cardiac increase of miR-526b-3p, and decrease of CD31 and CD34 in DOX-treated mice. The regulatory function of miR-526b-3p on cardiac function and cardiac microvessel density was detected via the transfection of miR-526b-3p mimics or inhibitor into Human Umbilical Vein Endothelial Cells (HUVECs) and the administration of rAAV in mice. HUVECs proliferation, apoptosis, tube formation, and migration were inspected by EdU, flow cytometry, tube formation and transwell assays. MiR-526b-3p was anti-proliferative but apoptosis-initiating in HUVECs, and aggravated cardiac abnormalities caused by DOX. Mechanically, the relationship between miR-526b-3p and VEGFA was disclosed by qRT-PCR. VEGFA and STAT3 interaction was confirmed by ChIP and luciferase reporter assay. MiR-526b-3p targeted STAT3 to reduce VEGFA transcription. We designed rescue assays and presented that the negative effects of miR-526b-3p on cardiac dysfunction and HUVECs were rescued by VEGFA reintroduction in DOX-affected mice. Overall, miR-526b-3p accelerated doxorubicin-induced cardiotoxicity through modulating STAT3/VEGFA, highlighting that targeting miR-526b-3p as a potential method to protect against DOX-induced cardiac dysfunction.
Insights
Doxorubicin chemotherapy causes heart damage by increasing miR-526b-3p, which harms vascular cells and cardiac function. Targeting miR-526b-3p may protect against this doxorubicin-induced cardiotoxicity.
Area of Science:
- Cardiology
- Molecular Biology
- Oncology
Background:
- Doxorubicin (DOX) is a potent chemotherapeutic agent with known cardiotoxic side effects.
- The precise mechanisms underlying DOX-induced vascular homeostasis disruption are not fully understood.
Purpose of the Study:
- To elucidate the role of miR-526b-3p in doxorubicin-induced cardiotoxicity.
- To investigate the molecular pathways involved in miR-526b-3p-mediated cardiac dysfunction.
Main Methods:
- Quantitative real-time PCR (qRT-PCR) and immunohistochemistry in DOX-treated mice.
- In vitro studies using Human Umbilical Vein Endothelial Cells (HUVECs) transfected with miR-526b-3p mimics/inhibitors.
- In vivo studies using rAAV administration in mice.
- Cell proliferation, apoptosis, tube formation, and migration assays.
- Chromatin immunoprecipitation (ChIP) and luciferase reporter assays.
Main Results:
- DOX treatment increased cardiac miR-526b-3p levels and decreased CD31/CD34 expression in mice.
- miR-526b-3p inhibited HUVEC proliferation and promoted apoptosis, while impairing tube formation and migration.
- miR-526b-3p targeted STAT3, leading to reduced VEGFA transcription.
- VEGFA reintroduction rescued DOX-induced cardiac dysfunction and HUVEC abnormalities.
Conclusions:
- miR-526b-3p exacerbates doxorubicin-induced cardiotoxicity by targeting the STAT3/VEGFA pathway.
- Targeting miR-526b-3p presents a potential therapeutic strategy to mitigate DOX-induced cardiac damage.
