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NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress
Yi Wang1,2, Yuxin Zan1, Yingying Huang1
1Hubei Key Laboratory of Embryonic Stem Cell Research, Taihe Hospital, Hubei University of Medicine, 442000, Shiyan, Hubei, China.
Abstract:
Doxorubicin (DOX) is a commonly used antitumor drug, but its application has been limited because of its strong cardiac damage. This study aims to explore the role of NSUN2 in DOX-induced heart injury. C57BL/6J mice were intraperitoneally injected with 20 mg/Kg DOX to induce heart injury. After 3 days, the cardiac function, cardiac histopathology, myocardial apoptosis, and the expression level of NSUN2 were detected. In vitro, H9C2 cells were transfected with NSUN2 siRNA or overexpressed lentivirus and then treated with 500 ng/ml DOX. After 24 h, the changes in reactive oxygen species (ROS), apoptosis, and NSUN2 expression were detected. After DOX treatment, both in vitro and in vivo experiments showed that the cardiac function decreased, the number of apoptotic cells increased, and the expression level of NSUN2 increased. Interfering the expression of NSUN2 by siRNA promoted DOX-induced heart injury, while overexpression of NSUN2 could inhibit DOX-induced heart injury. Further study showed that NSUN2 promoted antioxidative stress by upregulating the Nrf2 protein level. In addition, NSUN2 overexpression could increase the half-life of Nrf2 mRNA. m5C RNA methylation immunoprecipitation (MeRIP) also showed that the level of Nrf2 m5C mRNA was significantly increased in NSUN2 overexpressed group when compared to the GFP group. NSUN2 enhances the expression of Nrf2 by promoting Nrf2 mRNA m5C modification and enhances its antioxidative stress effect to alleviate DOX-induced myocardial injury.
Insights
The study reveals that NSUN2 protects against Doxorubicin-induced heart injury by enhancing the antioxidant Nrf2 pathway through mRNA modification. Upregulating NSUN2 can mitigate chemotherapy-related cardiotoxicity.
Area of Science:
- Cardiology
- Molecular Biology
- Oncology
Background:
- Doxorubicin (DOX) is a vital chemotherapy agent, but its clinical use is hampered by significant cardiotoxicity.
- The molecular mechanisms underlying DOX-induced myocardial injury require further elucidation to develop protective strategies.
Purpose of the Study:
- To investigate the role of NSUN2 (NOP2 RNA methyltransferase) in Doxorubicin-induced heart injury.
- To explore the potential of NSUN2 as a therapeutic target for mitigating Doxorubicin cardiotoxicity.
Main Methods:
- In vivo studies using C57BL/6J mice treated with Doxorubicin to assess cardiac function, histopathology, and NSUN2 expression.
- In vitro experiments using H9C2 cells with NSUN2 knockdown (siRNA) or overexpression (lentivirus) followed by Doxorubicin treatment to evaluate reactive oxygen species (ROS) and apoptosis.
- Mechanistic studies including Nrf2 protein and mRNA analysis, mRNA half-life assays, and m5C RNA methylation immunoprecipitation (MeRIP).
Main Results:
- Doxorubicin treatment led to decreased cardiac function, increased myocardial apoptosis, and elevated NSUN2 expression in both in vivo and in vitro models.
- NSUN2 knockdown exacerbated Doxorubicin-induced heart injury, while NSUN2 overexpression conferred protection.
- NSUN2 upregulated Nrf2 protein levels and increased the half-life of Nrf2 mRNA by promoting Nrf2 mRNA m5C modification, thereby enhancing antioxidative stress.
Conclusions:
- NSUN2 plays a protective role against Doxorubicin-induced cardiotoxicity.
- NSUN2 alleviates Doxorubicin-induced myocardial injury by upregulating Nrf2 expression via m5C mRNA modification, enhancing antioxidative defense.
- Targeting NSUN2 may represent a novel therapeutic strategy to prevent or treat Doxorubicin-related heart damage.
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