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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Activation of miR-34a-5p/Sirt1/p66shc pathway contributes to doxorubicin-induced cardiotoxicity
Jie-Ning Zhu1,2, Yong-Heng Fu1,2, Zhi-Qin Hu1,2
1Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Clinical Pharmacology, Guangzhou, 510080, China.
Abstract:
The molecular mechanisms underlying anthracyclines-induced cardiotoxicity have not been well elucidated. MiRNAs were revealed dysregulated in the myocardium and plasma of rats received Dox treatment. MicroRNA-34a-5p (miR-34a-5p) was verified increased in the myocardium and plasma of Dox-treated rats, but was reversed in rats received Dox plus DEX treatments. Human miR-34a-5p was also observed increased in the plasma of patients with diffuse large B-cell lymphoma after 9- and 16-week epirubicin therapy. Up-regulation of miR-34a-5p was observed in Dox-induced rat cardiomyocyte H9c2 cells. MiR-34a-5p could augment Bax expression, but inhibited Bcl-2 expression, along with the increases of the activated caspase-3 and mitochondrial potentials in H9C2 cells. MiR-34a-5p was verified to modulate Sirt1 expression post-transcriptionally. In parallel to Sirt1 siRNA, miR-34a-5p could enhance p66shc expression, accompanied by increases of Bax and the activated caspase-3 and a decrease of Bcl-2 in H9c2 cells. Moreover, enforced expression of Sirt1 alleviated Dox-induced apoptosis of H9c2 cells, with suppressing levels of p66shc, Bax, the activated caspase-3 and miR-34a-5p, and enhancing Bcl-2 expression. Therefore, miR-34a-5p enhances cardiomyocyte apoptosis by targeting Sirt1, activation of miR-34a-5p/Sirt1/p66shc pathway contributes to Dox-induced cardiotoxicity, and blockage of this pathway represents a potential cardioprotective effect against anthracyclines.
Insights
MicroRNA-34a-5p (miR-34a-5p) activation contributes to Doxorubicin-induced cardiotoxicity by targeting Sirtuin 1 (Sirt1). Blocking this miR-34a-5p/Sirt1 pathway may offer cardioprotection against anthracyclines.
Area of Science:
- Molecular Biology
- Cardiology
- Oncology
Background:
- Anthracyclines are widely used chemotherapy agents but can cause cardiotoxicity.
- The precise molecular mechanisms of anthracycline-induced cardiotoxicity remain unclear.
- MicroRNAs (miRNAs) are implicated in cardiac function and disease.
Purpose of the Study:
- To elucidate the role of microRNA-34a-5p (miR-34a-5p) in anthracycline-induced cardiotoxicity.
- To investigate the molecular targets and pathways affected by miR-34a-5p in cardiomyocytes.
- To explore potential cardioprotective strategies against anthracycline cardiotoxicity.
Main Methods:
- Animal models treated with Doxorubicin (Dox) and Dexamethasone (DEX).
- In vitro studies using H9c2 rat cardiomyocyte cell line.
- Analysis of miRNA expression, protein levels (Bax, Bcl-2, caspase-3, Sirt1, p66shc), and mitochondrial potential.
- Gene silencing (siRNA) and overexpression techniques.
Main Results:
- miR-34a-5p was upregulated in Dox-treated rat myocardium and plasma, and in H9c2 cells.
- miR-34a-5p promoted apoptosis by increasing Bax and decreasing Bcl-2, activating caspase-3.
- miR-34a-5p post-transcriptionally targeted Sirtuin 1 (Sirt1), leading to increased p66shc expression.
- Sirt1 overexpression alleviated Dox-induced apoptosis, reducing p66shc, Bax, and caspase-3, while increasing Bcl-2.
Conclusions:
- miR-34a-5p enhances cardiomyocyte apoptosis by targeting Sirt1.
- The miR-34a-5p/Sirt1/p66shc pathway is activated in Dox-induced cardiotoxicity.
- Inhibition of this pathway holds potential for cardioprotection against anthracyclines.
