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Involvement of ROS/NLRP3 Inflammasome Signaling Pathway in Doxorubicin-Induced Cardiotoxicity

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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.

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Acknowledgements

This work was supported by Grants of the National Natural Scientific Foundation of China (Nos. 81703518, 81973406, 81773734, 81701577), Hunan Provincial Natural Scientific Foundation (Nos. 2018JJ3571, 2019JJ50849, 2020JJ4823), Fundamental Research Funds for the Central Universities of Central South University (No. 2020zzts822),  and Scientific Research Project of Hunan Provincial Health and Family Planning Commission (No. B20180253).

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Correspondence to Bikui Zhang or Wenqun Li.

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Wei, S., Ma, W., Li, X. et al. Involvement of ROS/NLRP3 Inflammasome Signaling Pathway in Doxorubicin-Induced Cardiotoxicity. Cardiovasc Toxicol 20, 507–519 (2020). https://doi.org/10.1007/s12012-020-09576-4

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