The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis
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, 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
Abstract
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.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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Source: PubMed