title: Role of HMGB1 in doxorubicin-induced myocardial apoptosis and its regulation pathway.
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.
authors.affiliation: Division of Cardiology, Department of Medicine, The Affiliated People's Hospital of Jiangsu University, No. 8 Dianli Road, Zhenjiang, 212002, Jiangsu Province, People's Republic of China.
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Yao
authors.forename: Xuemei
authors.initials: X
authors.lastname: Xu
authors.forename: Guohui
authors.initials: G
authors.lastname: Zhang
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Qian
authors.forename: Tao
authors.initials: T
authors.lastname: Rui
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004317:Doxorubicin; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D030421:Peroxynitrous Acid / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; D024243:HMGB1 Protein; D047428:Protein Kinase Inhibitors; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D030421:Peroxynitrous Acid; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases