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Published on: June 15, 2018
MicroRNA-22 inhibition prevents doxorubicin-induced cardiotoxicity via upregulating SIRT1
Can Xu1, Chang-Hui Liu1, Da-Li Zhang2
1Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan, 421001, PR China.
Abstract:
Oxidative stress and cardiomyocyte apoptosis contributed to the progression of doxorubicin (Dox)-induced cardiotoxicity. Recent studies identified microRNA-22 (miR-22) as a cardiac- and skeletal muscle-enriched microRNA that functioned as a key regulator in stress-induced cardiac injury. The present study aimed to investigate the role and possible mechanism of miR-22 on Dox-induced oxidative stress and cardiomyocyte apoptosis. Mice were exposed to reduplicative injections of Dox (i.p., 4 mg/kg) weekly for consecutive 4 weeks to generate Dox-induced cardiotoxicity. Herein, we found that miR-22 level was significantly increased in murine hearts subjected to chronic Dox treatment. MiR-22 inhibition attenuated oxidative stress and cardiomyocyte apoptosis in vivo and in vitro, thereby preventing Dox-induced cardiac dysfunction. Mechanistically, we observed that miR-22 directly bound to the 3'-UTR of Sirt1 and caused SIRT1 downregulation. Conversely, miR-22 antagomir upregulated SIRT1 expression and SIRT1 inhibitor abolished the beneficial effects of miR-22 antagomir. In conclusion, miR-22 inhibition prevented oxidative stress and cardiomyocyte apoptosis via upregulating SIRT1 and miR-22 might be a new target for treating Dox-induced cardiotoxicity.
Insights
Inhibiting microRNA-22 (miR-22) protects against doxorubicin-induced cardiotoxicity by reducing oxidative stress and cardiomyocyte apoptosis. This occurs through the upregulation of SIRT1, suggesting miR-22 as a potential therapeutic target.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Doxorubicin (Dox)-induced cardiotoxicity is a significant clinical challenge.
- Oxidative stress and cardiomyocyte apoptosis are key mechanisms driving Dox cardiotoxicity.
- MicroRNA-22 (miR-22) is implicated in stress-induced cardiac injury.
Purpose of the Study:
- To investigate the role of miR-22 in Dox-induced cardiotoxicity.
- To elucidate the underlying mechanism of miR-22 in regulating oxidative stress and apoptosis.
- To evaluate miR-22 as a potential therapeutic target.
Main Methods:
- Mice received weekly doxorubicin injections for 4 weeks to induce cardiotoxicity.
- miR-22 levels were assessed in cardiac tissues.
- In vivo and in vitro experiments were conducted to assess the effects of miR-22 inhibition.
- Mechanistic studies involved analyzing miR-22 binding to Sirt1 and its impact on SIRT1 expression.
Main Results:
- Chronic doxorubicin treatment significantly increased miR-22 levels in murine hearts.
- Inhibition of miR-22 attenuated oxidative stress and cardiomyocyte apoptosis, improving cardiac function.
- miR-22 directly downregulates SIRT1 expression by binding to its 3'-UTR.
- Upregulation of SIRT1 by miR-22 antagomir was reversed by a SIRT1 inhibitor.
Conclusions:
- miR-22 inhibition ameliorates doxorubicin-induced cardiotoxicity.
- The protective effect is mediated by the upregulation of SIRT1.
- miR-22 represents a promising therapeutic target for managing doxorubicin-induced cardiotoxicity.
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