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Role of HMGB1 in Doxorubicin‐induced myocardial apoptosis and its regulation pathway
Author(s) -
Yao Yongwei,
Zhang Guohui,
Zhang Yingyu,
Rui Tao
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1036.16
Subject(s) - hmgb1 , peroxynitrite , apoptosis , doxorubicin , kinase , chemistry , signal transduction , phosphorylation , p38 mitogen activated protein kinases , pharmacology , cancer research , tlr4 , microbiology and biotechnology , medicine , protein kinase a , biology , chemotherapy , biochemistry , receptor , enzyme , superoxide
The underlying mechanism by which Doxorubicin (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 apoptosis, and signal pathway involved in regulation of HMGB1 expression in cardiomyocytes with DOX. Methods and Results Treatment of 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 dysfunction. In addition, 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. Conclusion the 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. (Supported by National Science Foundation of China# 81170210).