Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Institute of Clinical Pharmacy, Central South University, Changsha, 410011, Hunan, China.
Cardiovasc Toxicol. 2020 Oct;20(5):507-519. doi: 10.1007/s12012-020-09576-4.
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.
多柔比星（Dox）广泛用于癌症治疗，但由于其心脏毒性，临床应用受到限制。多柔比星诱导的心脏毒性的潜在机制尚不清楚。本研究旨在评估 NLRP3 炎性体在多柔比星诱导的心脏毒性中的作用。NLRP3 炎性体在接受多柔比星（5mg/kg，每两天一次，累积剂量为 15mg/kg，并在最后一次多柔比星注射后 2 天处死）治疗的 C57BL/6 小鼠的心肌中被激活，表现为 NLRP3 和 Caspase-1 p20 的上调。多柔比星（1μM，48h）同时诱导 H9c2 细胞和原代心肌细胞凋亡，伴随着 NLRP3、ASC 和 Caspase-1 p20 表达的上调，以及 IL-1β 的分泌增加，提示 NLRP3 炎性体的激活。MCC950（NLRP3 的特异性抑制剂）可逆转多柔比星对 H9c2 细胞和原代心肌细胞的这些作用。鉴于 ROS 在多柔比星诱导的心脏毒性中的关键作用，进一步研究了 ROS 与 NLRP3 之间的关系。在用多柔比星处理后，心肌、H9c2 细胞和原代心肌细胞中的 ROS 水平增加。用 NAC 降低 ROS 水平可抑制多柔比星处理的 H9c2 细胞和原代心肌细胞中 NLRP3 炎性体的激活、IL-1β 的分泌和凋亡。总之，本研究揭示了 ROS/NLRP3 相关炎性体激活在多柔比星诱导的心脏毒性中的关键作用，NLRP3 炎性体可能成为多柔比星诱导的心脏毒性的新治疗靶点。
