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Basic Research in Cardiology
Erschienen in: Basic Research in Cardiology 6/2010

01.11.2010 | Original Contribution

HMGB1: the missing link between diabetes mellitus and heart failure

verfasst von: H. Christian Volz, Cathrin Seidel, Danai Laohachewin, Ziya Kaya, Oliver J. Müller, Sven T. Pleger, Felix Lasitschka, Marco E. Bianchi, Andrew Remppis, Angelika Bierhaus, Hugo A. Katus, Martin Andrassy

Erschienen in: Basic Research in Cardiology | Ausgabe 6/2010

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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.
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Metadaten
Titel
HMGB1: the missing link between diabetes mellitus and heart failure
verfasst von
H. Christian Volz
Cathrin Seidel
Danai Laohachewin
Ziya Kaya
Oliver J. Müller
Sven T. Pleger
Felix Lasitschka
Marco E. Bianchi
Andrew Remppis
Angelika Bierhaus
Hugo A. Katus
Martin Andrassy
Publikationsdatum
01.11.2010
Verlag
Springer-Verlag
Erschienen in
Basic Research in Cardiology / Ausgabe 6/2010
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI
https://doi.org/10.1007/s00395-010-0114-3

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