title: The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis.
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.
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Heinzmann
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Bangert
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Müller
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Saskia N I
authors.initials: SN
authors.lastname: von Ungern-Sternberg
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Frederic
authors.initials: F
authors.lastname: Emschermann
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönberger
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Institute of Anatomy, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Mack
authors.affiliation: Institute for Pathology and Neuropathology, Department of Molecular Pathology, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.affiliation: Institute for Pathology and Neuropathology, Department of Molecular Pathology, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kandolf
authors.affiliation: Martin-Luther-Universität Halle-Wittenberg, Institut für Biochemie, Abteilung Enzymologie, Projektgruppe gFP5, Halle (Saale), Germany.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Malesevic
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Harald F
authors.initials: HF
authors.lastname: Langer
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hugo
authors.initials: H
authors.lastname: Katus
authors.affiliation: Max-Planck-Institut für Biophysikalische Chemie Göttingen, BO Halle (Saale), Göttingen, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Andreas E
authors.initials: AE
authors.lastname: May
authors.affiliation: Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ziya
authors.initials: Z
authors.lastname: Kaya
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls Universität Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Seizer
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D021984:Cyclophilin A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000737:chemistry*; D005355:Fibrosis; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D009205:Myocarditis / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects; D019210:Troponin I; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D003524:Cyclosporins; D015850:Interleukin-6; D019210:Troponin I; D014409:Tumor Necrosis Factor-alpha; C000599101:cyclosporine A, 4-((6-carboxy-1H-benzo(d)imidazol-2-yl)methyl)-4-methylthreonine)(1)-; D020780:Matrix Metalloproteinase 9; D021984:Cyclophilin A