title: HMGB1: the missing link between diabetes mellitus and heart failure.
abstract: Diabetes mellitus (DM) is a major independent risk factor for cardiovascular disease, but also leads to cardiomyopathy. However, the etiology of the cardiac disease is unknown. Therefore, the aim of this study was to identify molecular mechanisms underlying diabetic heart disease. High glucose treatment of isolated cardiac fibroblasts, macrophages and cardiomyocytes led to a sustained induction of HMGB1 on the RNA and protein level followed by increased NF-κB binding activity with consecutively sustained TNF-α and IL-6 expression. Short interference (si) RNA knock-down for HMGB1 and RAGE in vitro confirmed the importance of this axis in diabetes-driven chronic inflammation. In a murine model of post-myocardial infarction remodeling in type 1 diabetes, cardiac HMGB1 expression was significantly elevated both on RNA and protein level paralleled by increased expression of pro-inflammatory cytokines up to 10 weeks. HMGB1-specific blockage via box A treatment significantly reduced post-myocardial infarction remodeling and markers of tissue damage in vivo. The protective effects of box A indicated an involvement of the mitogen-activated protein-kinases jun N-terminal kinase and extracellular signal-regulated kinase 1/2, as well as the transcription factor nuclear factor-kappaB. Interestingly, remodeling and tissue damage were not affected by administration of box A in RAGE(-/-) mice. In conclusion, HMGB1 plays a major role in DM and post-I/R remodeling by binding to RAGE, resulting in activation of sustained pro-inflammatory pathways and enhanced myocardial injury. Therefore, blockage of HMGB1 might represent a therapeutic strategy to reduce post-ischemic remodeling in DM.
authors: Department of Medicine III, University of Heidelberg, INF 410, 69120, Heidelberg, Germany.
authors: H Christian
authors: HC
authors: Volz
authors: Cathrin
authors: C
authors: Seidel
authors: Danai
authors: D
authors: Laohachewin
authors: Ziya
authors: Z
authors: Kaya
authors: Oliver J
authors: OJ
authors: Müller
authors: Sven T
authors: ST
authors: Pleger
authors: Felix
authors: F
authors: Lasitschka
authors: Marco E
authors: ME
authors: Bianchi
authors: Andrew
authors: A
authors: Remppis
authors: Angelika
authors: A
authors: Bierhaus
authors: Hugo A
authors: HA
authors: Katus
authors: Martin
authors: M
authors: Andrassy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D024243:HMGB1 Protein / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors; D014162:Transfection; D020257:Ventricular Remodeling
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018836:Inflammation Mediators; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose