Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway
Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway
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HMGB1在阿霉素诱导心肌细胞凋亡中的作用及其调控途径
DOI：
10.1007/s00395-012-0267-3
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发表时间：
2012-05-01
影响因子：
9.5
通讯作者：
Rui, Tao
中科院分区：
文献类型：
--
作者：
Yao, Yongwei;Xu, Xuemei;Rui, Tao
多柔比星（DOX）是一种广泛应用的抗肿瘤药物。但其副作用可引起心肌细胞凋亡和心功能不全，限制了其临床应用。然而，DOX引起心肌细胞凋亡的潜在机制尚不清楚。本研究旨在探讨高迁移率族蛋白B1（HMGB 1）在阿霉素心肌损伤中的作用，以及HMGB 1在阿霉素心肌损伤中的调控信号通路。我们发现用DOX处理分离的心肌细胞和幼稚小鼠导致HMGB 1表达增加，这与心肌细胞凋亡增加有关。药物（A-box）或基因阻断（TLR 4缺陷，TLR 4（-/-））HMGB 1可减轻DOX诱导的心肌细胞凋亡和心功能不全。此外，我们的研究表明，DOX导致过氧亚硝酸盐（ONOO-）的产生增加和c-Jun N末端激酶（JNK）磷酸化的升高。用过氧亚硝酸盐分解催化剂FeTPPS预处理心肌细胞，可阻止DOX诱导的JNK磷酸化、HMGB 1表达、心肌细胞凋亡和心功能不全。JNK的遗传（JNK（-/-））或药理学（SP 600125）抑制可改善DOX诱导的HMGB 1表达，减少心肌细胞凋亡和心功能障碍。以上结果提示HMGB 1介导了DOX诱导的心肌损伤，ONOO-/JNK是DOX诱导心肌HMGB 1表达的重要调控途径。
Doxorubicin (DOX) is a widely used antitumor agent. The clinical application of the medication is limited by its side effect which can elicit myocardial apoptosis and cardiac dysfunction. However, the underlying mechanism by which DOX causes cardiomyocyte apoptosis is not clear. The aim of present study is to investigate the role of high-mobility group box 1 (HMGB1) in DOX-induced myocardial injury, and signal pathway involved in regulation of HMGB1 expression in cardiomyocytes with DOX. We found treatment of isolated cardiomyocytes and naive mice with the DOX resulted in an increased HMGB1 expression which was associated with increased myocardial cell apoptosis. Pharmacological (A-box) or genetic blockade (TLR4 deficiency, TLR4(-/-)) of HMGB1 attenuated the DOX-induced myocardial apoptosis and cardiac dysfunction. In addition, our study showed that DOX resulted in an increment in the generation of peroxynitrite (ONOO-) and an elevation in phosphorylation of c-Jun N terminal kinase (JNK). Pretreatment of myocytes with FeTPPS, a peroxynitrite decomposition catalyst, prevented DOX-induced JNK phosphorylation, HMGB1 expression, myocardial apoptosis and cardiac dysfunction. Genetic (JNK(-/-)) or pharmacological (SP600125) inhibition of JNK ameliorated the DOX-induced HMGB1 expression and diminished myocardial apoptosis and cardiac dysfunction. Taken together, our results indicate that HMGB1 mediates the myocardial injury induced by DOX and ONOO-/JNK is a key regulatory pathway of myocardial HMGB1 expression induced by DOX.