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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.
- Source :
-
PloS one [PLoS One] 2015 Apr 20; Vol. 10 (4), pp. e0124606. Date of Electronic Publication: 2015 Apr 20 (Print Publication: 2015). - Publication Year :
- 2015
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 25894208
- Full Text :
- https://doi.org/10.1371/journal.pone.0124606