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The novel extracellular Cyclophilin A (CyPA)-inhibitor MM284 reduces myocardial inflammation and remodeling in a mouse model of Troponin I-induced myocarditis

Cyclophilins are a group of highly conserved cytosolic enzymes that have a peptidylprolyl cis/trans isomerase activity. Cyclophilin A (CyPA) can be secreted in the extracellular space by inflammatory cells and upon cell death. The presence of CyPA in patients with non-ischemic cardiomyopathy is asso...

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Main Authors: Heinzmann, David (Author) , Bangert, Anna (Author) , Müller, Anna-Maria (Author) , Ungern-Sternberg, Saskia N. I. von (Author) , Emschermann, Frederic (Author) , Schönberger, Tanja (Author) , Chatterjee, Madhumita (Author) , Mack, Andreas F. (Author) , Klingel, Karin (Author) , Kandolf, Reinhard (Author) , Malesevic, Miroslav (Author) , Borst, Oliver (Author) , Gawaz, Meinrad (Author) , Langer, Harald F. (Author) , Katus, Hugo (Author) , Fischer, Gunter (Author) , May, Andreas E. (Author) , Kaya, Ziya (Author) , Seizer, Peter (Author)
Format: Article (Journal)
Language:English
Published: April 20, 2015
In: PLOS ONE
Year: 2015, Volume: 10, Issue: 4
ISSN:1932-6203
DOI:10.1371/journal.pone.0124606
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1371/journal.pone.0124606
Verlag, lizenzpflichtig, Volltext: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124606
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Author Notes:David Heinzmann, Anna Bangert, Anna-Maria Müller, Saskia N.I. von Ungern-Sternberg, Frederic Emschermann, Tanja Schönberger, Madhumita Chatterjee, Andreas F. Mack, Karin Klingel, Reinhard Kandolf, Miroslav Malesevic, Oliver Borst, Meinrad Gawaz, Harald F. Langer, Hugo Katus, Gunter Fischer, Andreas E. May, Ziya Kaya, Peter Seizer
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Summary:Cyclophilins are a group of highly conserved cytosolic enzymes that have a peptidylprolyl cis/trans isomerase activity. Cyclophilin A (CyPA) can be secreted in the extracellular space by inflammatory cells and upon cell death. The presence of CyPA in patients with non-ischemic cardiomyopathy is associated with poor clinical prognosis. Here, we investigated the inhibition of extracellular CyPA in a mouse model of troponin I-induced autoimmune myocarditis using the strictly extracellular CyPA-inhibitor MM284. Since A/J mice develop severe inflammation and fibrosis after immunization with murine cardiac troponin I (mcTn I), we used this model to analyze the effects of an extracellular CyPA inhibition. As extracellular CyPA-inhibitor we used the recently described CsA-derivate MM284. In vitro studies confirmed that MM284 inhibits CyPA-induced monocytic migration and adhesion. A/J mice immunized with mcTnI were treated with MM284 or vehicle every second day. After 28 days, we found a considerable reduction of myocardial injury and fibrosis. Further analysis revealed a reduced myocardial presence of T-cells and macrophages compared to control treated animals. Whereas MMP-9 expression was reduced significantly by MM284, we observed no significant reduction of inflammatory cytokines such as IL-6 or TNFα. Extracellular CyPA plays an important role in autoimmune myocarditis for myocardial damage and fibrosis. Our data suggest a new pharmacological approach for the treatment of myocardial inflammation and reduction of cardiac fibrosis by inhibition of extracellular CyPA.
Item Description:Gesehen am 17.08.2020
Physical Description:Online Resource
ISSN:1932-6203
DOI:10.1371/journal.pone.0124606

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