Details

Autor(en) / Beteiligte

• Heinzmann, David
• Bangert, Anna
• Müller, Anna-Maria
• von Ungern-Sternberg, Saskia N I
• Emschermann, Frederic
• Schönberger, Tanja
• Chatterjee, Madhumita
• Mack, Andreas F
• Klingel, Karin
• Kandolf, Reinhard
• Malesevic, Miroslav
• Borst, Oliver
• Gawaz, Meinrad
• Langer, Harald F
• Katus, Hugo
• Fischer, Gunter
• May, Andreas E
• Kaya, Ziya
• Seizer, Peter
• Frangogiannis, Nikolaos

Titel

The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis

Ist Teil von

• PloS one, 2015-04, Vol.10 (4), p.e0124606-e0124606

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.