HMGB1: The missing link between diabetes mellitus and heart failure

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)805-820
Number of pages16
JournalBasic Research in Cardiology
Volume105
Issue number6
DOIs
Publication statusPublished - Nov 2010

Keywords

  • Diabetes
  • Heart failure
  • HMGB1
  • Inflammation
  • Post-myocardial infarction remodeling
  • RAGE

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Fingerprint Dive into the research topics of 'HMGB1: The missing link between diabetes mellitus and heart failure'. Together they form a unique fingerprint.

  • Cite this

    Volz, H. C., Seidel, C., Laohachewin, D., Kaya, Z., Müller, O. J., Pleger, S. T., Lasitschka, F., Bianchi, M. E., Remppis, A., Bierhaus, A., Katus, H. A., & Andrassy, M. (2010). HMGB1: The missing link between diabetes mellitus and heart failure. Basic Research in Cardiology, 105(6), 805-820. https://doi.org/10.1007/s00395-010-0114-3