1. The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis.
- Author
-
Heinzmann D, Bangert A, Müller AM, von Ungern-Sternberg SN, Emschermann F, Schönberger T, Chatterjee M, Mack AF, Klingel K, Kandolf R, Malesevic M, Borst O, Gawaz M, Langer HF, Katus H, Fischer G, May AE, Kaya Z, and Seizer P
- Subjects
- Animals, Autoimmune Diseases complications, Autoimmune Diseases drug therapy, Autoimmune Diseases pathology, Autoimmune Diseases physiopathology, Cell Adhesion drug effects, Cell Movement drug effects, Cyclophilin A metabolism, Cyclosporins pharmacology, Disease Models, Animal, Fibrosis, Humans, Inflammation complications, Interleukin-6 metabolism, Macrophages drug effects, Matrix Metalloproteinase 9 metabolism, Mice, Monocytes drug effects, Monocytes pathology, Myocarditis complications, Myocarditis pathology, Myocarditis physiopathology, T-Lymphocytes drug effects, Troponin I, Tumor Necrosis Factor-alpha metabolism, Cyclophilin A antagonists & inhibitors, Cyclosporins therapeutic use, Extracellular Space chemistry, Inflammation pathology, Myocarditis drug therapy, Myocardium pathology, Ventricular Remodeling drug effects
- 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.
- Published
- 2015
- Full Text
- View/download PDF