Involvement of ROS/NLRP3 Inflammasome Signaling Pathway in Doxorubicin-Induced Cardiotoxicity
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Involvement of ROS/NLRP3 Inflammasome Signaling Pathway in Doxorubicin‑Induced Cardiotoxicity Shanshan Wei1,2 · Wanjun Ma1,2 · Xiaohui Li3 · Chuanhao Jiang4 · Taoli Sun5 · Yuanjian Li3 · Bikui Zhang1,2 · Wenqun Li1,2
© Springer Science+Business Media, LLC, part of Springer Nature 2020
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 Doxinduced cardiotoxicity, and NLRP3 inflammasome may represent a new therapeutic target for Dox-induced cardiotoxicity.
Handling Editor: Yu-Ming Kang. Shanshan Wei and Wanjun Ma contributed equally to this work. * Bikui Zhang [email protected] * Wenqun Li [email protected] 1
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
2
Institute of Clinical Pharmacy, Central South University, Changsha 410011, Hunan, China
3
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410008, Hunan, China
4
Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, China
5
Key Laboratory Breeding Base of Hu’nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy, Changsha Medical University, Changsha 410219, Hunan, China
13
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Cardiovascular Toxicology
Graphic Abstract
Keywords Doxorubicin · Cardiomyocyte · Apoptosis · NLRP3 inflammasome · ROS
Introduction Doxorubicin (Dox) is the first anthracycline discovered in the 1960s, and it is now widely utilized in the therapy of solid and hematological malignancies [1]. However, the clinical application is limited by its side effects, especially dose-limiting card
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