Universität zu Köln

Bangert, Anna, Andrassy, Martin, Mueller, Anna-Maria, Bockstahler, Mariella, Fischer, Andrea, Volz, Christian H., Leib, Christoph, Goeser, Stefan, Korkmaz-Icoez, Sevil, Zittrich, Stefan, Jungmann, Andreas, Lasitschka, Felix, Pfitzer, Gabriele, Mueller, Oliver J., Katus, Hugo A. and Kaya, Ziya (2016). Critical role of RAGE and HMGB1 in inflammatory heart disease. Proc. Natl. Acad. Sci. U. S. A., 113 (2). S. E155 - 10. WASHINGTON: NATL ACAD SCIENCES. ISSN 0027-8424

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bangert, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Andrassy, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Anna-Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Bockstahler, Mariella UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Volz, Christian H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leib, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Goeser, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Korkmaz-Icoez, Sevil UNSPECIFIED UNSPECIFIED UNSPECIFIED Zittrich, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Jungmann, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Lasitschka, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfitzer, Gabriele UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Oliver J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Katus, Hugo A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaya, Ziya UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-287356
DOI:	10.1073/pnas.1522288113
Journal or Publication Title:	Proc. Natl. Acad. Sci. U. S. A.
Volume:	113
Number:	2
Page Range:	S. E155 - 10
Date:	2016
Publisher:	NATL ACAD SCIENCES
Place of Publication:	WASHINGTON
ISSN:	0027-8424
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOBILITY GROUP BOX-1; CARDIAC TROPONIN-I; ISCHEMIA-REPERFUSION INJURY; GLYCATION END-PRODUCTS; T-CELL-ACTIVATION; MYOCARDIAL-INFARCTION; GENE-TRANSFER; STEM-CELLS; RAT-HEART; RECEPTOR Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28735