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Updated: Oct 3, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
MicroRNA-495-3p diminishes doxorubicin-induced cardiotoxicity through activating AKT
1The First Affiliated Hospital, Functional Department, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
Abstract:
Doxorubicin (Dox) is a broad-spectrum antitumour agent; however, its clinical application is impeded due to the cumulative cardiotoxicity. The present study aims to investigate the role and underlying mechanisms of microRNA-495-3p (miR-495-3p) in Dox-induced cardiotoxicity. Herein, we found that cardiac miR-495-3p expression was significantly decreased in Dox-treated hearts, and that the miR-495-3p agomir could prevent oxidative stress, cell apoptosis, cardiac mass loss, fibrosis and cardiac dysfunction upon Dox stimulation. In contrast, the miR-495-3p antagomir dramatically aggravated Dox-induced cardiotoxicity in mice. Besides, we found that the miR-495-3p agomir attenuated, while the miR-495-3p antagomir exacerbated Dox-induced oxidative stress and cellular injury in vitro. Mechanistically, we demonstrated that miR-495-3p directly bound to the 3'-untranslational region of phosphate and tension homology deleted on chromosome ten (PTEN), downregulated PTEN expression and subsequently activated protein kinase B (PKB/AKT) pathway, and that PTEN overexpression or AKT inhibition completely abolished the cardioprotective effects of the miR-495-3p agomir. Our study for the first time identify miR-495-3p as an endogenous protectant against Dox-induced cardiotoxicity through activating AKT pathway in vivo and in vitro.
Insights
MicroRNA-495-3p (miR-495-3p) protects against Doxorubicin (Dox)-induced cardiotoxicity by downregulating PTEN and activating the AKT pathway. This finding offers a novel therapeutic strategy for mitigating Dox-induced heart damage.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Oncology
Background:
- Doxorubicin (Dox) is a potent anticancer drug, but its use is limited by dose-dependent cardiotoxicity.
- Understanding the molecular mechanisms of Dox-induced cardiotoxicity is crucial for developing protective strategies.
Purpose of the Study:
- To investigate the role of microRNA-495-3p (miR-495-3p) in Doxorubicin-induced cardiotoxicity.
- To elucidate the underlying molecular mechanisms of miR-495-3p's protective effects.
Main Methods:
- Assessed cardiac miR-495-3p expression in Dox-treated mice.
- Administered miR-495-3p agomir or antagomir to evaluate protective or aggravating effects on Dox-induced cardiotoxicity in vivo and in vitro.
- Investigated the direct binding of miR-495-3p to PTEN and its impact on the AKT pathway.
Main Results:
- Cardiac miR-495-3p expression was significantly reduced in Dox-treated hearts.
- miR-495-3p agomir administration attenuated Dox-induced oxidative stress, apoptosis, cardiac mass loss, fibrosis, and dysfunction.
- miR-495-3p directly targets PTEN, downregulating its expression and activating the AKT pathway, which mediates its cardioprotective effects.
Conclusions:
- miR-495-3p acts as an endogenous protectant against Doxorubicin-induced cardiotoxicity.
- The protective mechanism involves the miR-495-3p/PTEN/AKT signaling axis.
- Targeting miR-495-3p presents a potential therapeutic avenue for preventing Dox-induced heart damage.
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