Yao Yongwei, Chen Rong, Ying Chunyang, Zhang Guohui, Rui Tao, Tao Aibin
Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, ZhenJiang City, Jiangsu Province, 212002, China.
Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, ZhenJiang City, Jiangsu Province, 212002, China.
Biochem Biophys Res Commun. 2017 Nov 25;493(3):1288-1295. doi: 10.1016/j.bbrc.2017.09.153. Epub 2017 Sep 28.
Interleukin-33 (IL-33), a new member of the IL-1 cytokine family, has cardiac protective effect in many circumstances. The aims of present study are to assess whether IL-33 can protect cardiomyocytes from doxorubicin (DOX)-induced apoptosis and the mechanism involved in the protection. Cardiomyocytes derived from either wild-type or c-Jun N-terminal kinase deficient (JNK) mice were challenged with DOX (1 μM) with or without IL-33 (10 ng/ml). Myocyte apoptosis was assessed by measuring Caspase 3 activity, fragmented DNA and the TUNEL staining. In addition, cardiomyocyte reactive oxygen species (ROS) was assessed by measuring 2',7'-dichlorofluorescin diacetate (DCFDA); apoptosis signal-regulating kinase 1(ASK1) and JNK phosphorylation were assessed with western blot analysis. Treatment of cardiomyocyes with DOX resulted in ROS generation, ASK1 and JNK phosphorylation and myocyte apoptosis. IL-33 inhibited the DOX-induced ROS, prevented ASK1 and JNK phosphorylation and attenuated the DOX-induced myocyte apoptosis. Genetic inhibition of ASK1 (ASK1 siRNA transfection) and JNK (JNK) ameliorated the cardiac-protective effect of IL-33. Moreover, inhibition of ASK1 prevented the DOX-induced phosphorylation of JNK, while inhibition of JNK showed no effect on DOX-induced ASK1 phosphorylation. Our study indicates that: 1) ASK1/JNK signaling pathway is involved in DOX-induced cardiomyocyte apoptosis; 2) IL-33 protects cardiomyocytes from DOX-induced myocyte apoptosis through inhibition of the ASK1/JNK signaling pathway. IL-33 may have therapeutic potential for DOX-induced cardiac injury.
白细胞介素-33（IL-33）是白细胞介素-1细胞因子家族的新成员，在许多情况下具有心脏保护作用。本研究的目的是评估IL-33是否能保护心肌细胞免受阿霉素（DOX）诱导的凋亡以及保护作用的相关机制。用或不用IL-33（10 ng/ml）处理野生型或c-Jun氨基末端激酶缺陷（JNK）小鼠来源的心 肌细胞，并给予DOX（1 μM）。通过检测半胱天冬酶3活性、DNA片段化和TUNEL染色评估心肌细胞凋亡。此外，通过检测二氯二氢荧光素二乙酸酯（DCFDA）评估心肌细胞活性氧（ROS）；用蛋白质印迹分析评估凋亡信号调节激酶1（ASK1）和JNK磷酸化。用DOX处理心肌细胞导致ROS生成、ASK1和JNK磷酸化以及心肌细胞凋亡。IL-33抑制DOX诱导的ROS生成，阻止ASK1和JNK磷酸化，并减轻DOX诱导的心肌细胞凋亡。对ASK1（ASK1 siRNA转染）和JNK（JNK）进行基因抑制可改善IL-33的心脏保护作用。此外，抑制ASK1可阻止DOX诱导的JNK磷酸化，而抑制JNK对DOX诱导的ASK1磷酸化无影响。我们的研究表明：1）ASK1/JNK信号通路参与DOX诱导的心肌细胞凋亡；2）IL-
33通过抑制ASK1/JNK信号通路保护心肌细胞免受DOX诱导的心肌细胞凋亡。IL-33可能对DOX诱导的心脏损伤具有治疗潜力。
