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Updated: Dec 16, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Involvement of ROS/NLRP3 Inflammasome Signaling Pathway in Doxorubicin-Induced Cardiotoxicity
Shanshan Wei1,2, Wanjun Ma1,2, Xiaohui Li3
1Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Abstract:
Doxorubicin (Dox) is widely used in cancer therapy, but the clinical application is limited by its cardiotoxicity. The underlying mechanism of Dox-induced cardiotoxicity remains unclear. Present study aimed to evaluate the role of NLRP3 inflammasome in Dox-induced cardiotoxicity. The NLRP3 inflammasome was activated in the myocardium of Dox-treating (5 mg/kg, once every other day, cumulative dosage to 15 mg/kg and sacrificed after 2 days of last Dox injection) C57BL/6 mice as shown by the up-regulation of NLRP3 and Caspase-1 p20. Dox (1 μM for 48 h) induced the apoptosis of H9c2 cells and primary cardiomyocytes concomitantly with up-regulation of NLRP3, ASC and Caspase-1 p20 expressions, as well as the increased IL-1β secretion, suggesting the activation of NLRP3 inflammasome. These effects of Dox on H9c2 cells and primary cardiomyocytes can be reversed by MCC950, a specific inhibitor of NLRP3. In view of the key role of ROS on the Dox-induced cardiotoxicity, the relationship between ROS and NLRP3 was further investigated. The ROS level was increased in myocardium, H9c2 cells and primary cardiomyocytes after treating with Dox. Decreasing ROS level by NAC can inhibit the NLRP3 inflammasome activation, secretion of IL-1β and apoptosis in Dox-treating H9c2 cells and primary cardiomyocytes. Collectively, this study reveals a crucial role of ROS/NLRP3-associated inflammasome activation in Dox-induced cardiotoxicity, and NLRP3 inflammasome may represent a new therapeutic target for Dox-induced cardiotoxicity.
Insights
Doxorubicin (Dox) causes heart damage by activating the NLRP3 inflammasome, a process linked to reactive oxygen species (ROS). Inhibiting NLRP3 or ROS may protect against Dox-induced cardiotoxicity.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Toxicology
Background:
- Doxorubicin (Dox) is a vital chemotherapy agent.
- Dox-induced cardiotoxicity limits its clinical use.
- The precise mechanisms underlying Dox cardiotoxicity are not fully understood.
Purpose of the Study:
- To investigate the role of the NLRP3 inflammasome in Doxorubicin-induced cardiotoxicity.
- To explore the relationship between reactive oxygen species (ROS) and NLRP3 inflammasome activation in this context.
Main Methods:
- Activation of NLRP3 inflammasome in mouse myocardium and cultured cardiomyocytes (H9c2 cells, primary cardiomyocytes) treated with Dox.
- Assessment of NLRP3, Caspase-1, ASC, IL-1β, and ROS levels.
- Evaluation of the effects of MCC950 (NLRP3 inhibitor) and N-acetylcysteine (NAC, ROS scavenger).
Main Results:
- Dox treatment led to NLRP3 inflammasome activation in vivo and in vitro.
- Dox increased apoptosis and IL-1β secretion, which were reversed by MCC950.
- Dox elevated ROS levels; NAC treatment inhibited NLRP3 activation, IL-1β secretion, and apoptosis.
Conclusions:
- NLRP3 inflammasome activation plays a critical role in Doxorubicin-induced cardiotoxicity.
- Reactive oxygen species (ROS) are upstream activators of the ROS/NLRP3 inflammasome pathway in Dox cardiotoxicity.
- Targeting the NLRP3 inflammasome presents a potential therapeutic strategy for mitigating Dox-induced heart damage.
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