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01-05-2012 | Original Contribution

Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway

Authors: Yongwei Yao, Xuemei Xu, Guohui Zhang, Yingyu Zhang, Wei Qian, Tao Rui

Published in: Basic Research in Cardiology | Issue 3/2012

Abstract

Doxorubicin (DOX) is a widely used anti-tumor 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.

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Title: Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway
Authors: Yongwei Yao
Xuemei Xu
Guohui Zhang
Yingyu Zhang
Wei Qian
Tao Rui
Publication date: 01-05-2012
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 3/2012
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-012-0267-3

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Springer Medicine

Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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