Critical role of RAGE and HMGB1 in inflammatory heart disease
Myocardial inflammation leads in many cases to cardiomyopathy and contributes to progressive heart failure. The exact pathological mechanism of disease induction and progression in the setting of heart failure is unknown. High-mobility group box 1 (HMGB1), an evolutionarily abundant and highly conse...
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| Hauptverfasser: | , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2016
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| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 2016, Jahrgang: 113, Heft: 2, Pages: E155-E164 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.1522288113 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1073/pnas.1522288113 Verlag, Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720305/ 
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| Verfasserangaben: | Anna Bangert, Martin Andrassy, Anna-Maria Müller, Mariella Bockstahler, Andrea Fischer, Christian H. Volz, Christoph Leib, Stefan Göser, Sevil Korkmaz-Icöz, Stefan Zittrich, Andreas Jungmann, Felix Lasitschka, Gabriele Pfitzer, Oliver J. Müller, Hugo A. Katus, Ziya Kaya |
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| 245 | 1 | 0 | |a Critical role of RAGE and HMGB1 in inflammatory heart disease |c Anna Bangert, Martin Andrassy, Anna-Maria Müller, Mariella Bockstahler, Andrea Fischer, Christian H. Volz, Christoph Leib, Stefan Göser, Sevil Korkmaz-Icöz, Stefan Zittrich, Andreas Jungmann, Felix Lasitschka, Gabriele Pfitzer, Oliver J. Müller, Hugo A. Katus, Ziya Kaya |
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| 500 | |a Published online: December 29, 2015 | ||
| 500 | |a Gesehen am 13.03.2019 | ||
| 520 | |a Myocardial inflammation leads in many cases to cardiomyopathy and contributes to progressive heart failure. The exact pathological mechanism of disease induction and progression in the setting of heart failure is unknown. High-mobility group box 1 (HMGB1), an evolutionarily abundant and highly conserved protein, promotes cardiac inflammation, and in turn immunity, as a damage-associated molecular pattern. HMGB1 stimulates immunity, at least in part, through interaction with its principal binding partner RAGE (receptor for advanced glycation end products). Here we show that HMGB1 and RAGE appear to be important components in cardiac troponin I-induced experimental autoimmune myocarditis as well as in patients with myocarditis. Both molecules represent potential drug targets and show significant potential in heart failure treatment., Autoimmune response to cardiac troponin I (TnI) induces inflammation and fibrosis in the myocardium. High-mobility group box 1 (HMGB1) is a multifunctional protein that exerts proinflammatory activity by mainly binding to receptor for advanced glycation end products (RAGE). The involvement of the HMGB1-RAGE axis in the pathogenesis of inflammatory cardiomyopathy is yet not fully understood. Using the well-established model of TnI-induced experimental autoimmune myocarditis (EAM), we demonstrated that both local and systemic HMGB1 protein expression was elevated in wild-type (wt) mice after TnI immunization. Additionally, pharmacological inhibition of HMGB1 using glycyrrhizin or anti-HMGB1 antibody reduced inflammation in hearts of TnI-immunized wt mice. Furthermore, RAGE knockout (RAGE-ko) mice immunized with TnI showed no structural or physiological signs of cardiac impairment. Moreover, cardiac overexpression of HMGB1 using adeno-associated virus (AAV) vectors induced inflammation in the hearts of both wt and RAGE-ko mice. Finally, patients with myocarditis displayed increased local and systemic HMGB1 and soluble RAGE (sRAGE) expression. Together, our study highlights that HMGB1 and its main receptor, RAGE, appear to be crucial factors in the pathogenesis of TnI-induced EAM, because inhibition of HMGB1 and ablation of RAGE suppressed inflammation in the heart. Moreover, the proinflammatory effect of HMGB1 is not necessarily dependent on RAGE only. Other receptors of HMGB1 such as Toll-like receptors (TLRs) may also be involved in disease pathogenesis. These findings could be confirmed by the clinical relevance of HMGB1 and sRAGE. Therefore, blockage of one of these molecules might represent a novel therapeutic strategy in the treatment of autoimmune myocarditis and inflammatory cardiomyopathy. | ||
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