title: HMGB1 mediates hyperglycaemia-induced cardiomyocyte apoptosis via ERK/Ets-1 signalling pathway.
abstract: Apoptosis is a key event involved in diabetic cardiomyopathy. The expression of high mobility group box 1 protein (HMGB1) is up-regulated in diabetic mice. However, the molecular mechanism of high glucose (HG)-induced cardiomyocyte apoptosis remains obscure. We aimed to determine the role of HMGB1 in HG-induced apoptosis of cardiomyocytes. Treating neonatal primary cardiomyocytes with HG increased cell apoptosis, which was accompanied by elevated levels of HMGB1. Inhibition of HMGB1 by short-hairpin RNA significantly decreased HG-induced cell apoptosis by reducing caspase-3 activation and ratio of Bcl2-associated X protein to B-cell lymphoma/leukemia-2 (bax/bcl-2). Furthermore, HG activated E26 transformation-specific sequence-1 (Ets-1), and HMGB1 inhibition attenuated HG-induced activation of Ets-1 via extracellular signal-regulated kinase 1/2 (ERK1/2) signalling. In addition, inhibition of Ets-1 significantly decreased HG-induced cardiomyocyte apoptosis. Similar results were observed in streptozotocin-treated diabetic mice. Inhibition of HMGB1 by short-hairpin RNA markedly decreased myocardial cell apoptosis and activation of ERK and Ets-1 in diabetic mice. In conclusion, inhibition of HMGB1 may protect against hyperglycaemia-induced cardiomyocyte apoptosis by down-regulating ERK-dependent activation of Ets-1.
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Wen-Ke
authors.initials: WK
authors.lastname: Wang
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Lu
authors.forename: Jia-Ning
authors.initials: JN
authors.lastname: Zhang
authors.forename: Ben
authors.initials: B
authors.lastname: Wang
authors.forename: Xiang-Juan
authors.initials: XJ
authors.lastname: Liu
authors.forename: Feng-Shuang
authors.initials: FS
authors.lastname: An
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Qin
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: Chen
authors.forename: Wen-Qian
authors.initials: WQ
authors.lastname: Dong
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ming-Xiang
authors.initials: MX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000473:pathology; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C494042:Ets1 protein, mouse; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Ets-1; HMGB1; apoptosis; cardiomyocyte; diabetes; high glucose