title: Cyclophilin A affects inflammation, virus elimination and myocardial fibrosis in coxsackievirus B3-induced myocarditis.
abstract: Extracellular cyclophilin A (CyPA) and its receptor Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, CD147) modulate inflammatory processes beyond metalloproteinase (MMP) activity. Recently, we have shown that CyPA and CD147 are upregulated in patients with inflammatory cardiomyopathy. Here we investigate the role of CyPA and CD147 in murine coxsackievirus B3 (CVB3)-induced myocarditis. CVB3-infected CyPA(-/-) mice (129S6/SvEv) revealed a significantly reduced T-cell and macrophage recruitment at 8 days p.i. compared to wild-type mice. In A.BY/SnJ mice, treatment with the cyclophilin-inhibitor NIM811 was associated with a reduction of inflammatory lesions and MMP-9 expression but with enhanced virus replication 8 days p.i. At 28 days p.i. the extent of lesion areas was not affected bei NIM811, whereas the collagen content was reduced. Initiation of NIM811-treatment on day 12 (after an effective virus defense) resulted in an even more pronounced reduction of myocardial fibrosis. In conclusion, in CVB3-induced myocarditis CyPA is important for macrophage and T cell recruitment and effective virus defense and may represent a pharmacological target to modulate myocardial remodeling in myocarditis.
authors.affiliation: Medizinische Klinik III, Kardiologie und Kreislauferkrankungen, Eberhard Karls-Universität Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Seizer
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.forename: Martina
authors.initials: M
authors.lastname: Sauter
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Carmen
authors.initials: C
authors.lastname: Ochmann
authors.forename: Tanja
authors.initials: T
authors.lastname: Schönberger
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schleicher
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Stellos
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schmidt
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.forename: Boris
authors.initials: B
authors.lastname: Bigalke
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kandolf
authors.forename: Harald
authors.initials: H
authors.lastname: Langer
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.forename: Andreas E
authors.initials: AE
authors.lastname: May
mesh_terms: D000818:Animals; D051926:Basigin / Q000378:metabolism; D002460:Cell Line; D003384:Coxsackievirus Infections / Q000276:immunology*; D021984:Cyclophilin A / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004719:Endomyocardial Fibrosis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D029822:Enterovirus B, Human / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009205:Myocarditis / Q000150:complications / Q000276:immunology* / Q000821:virology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D051926:Basigin; D016572:Cyclosporine; C090438:(melle-4)cyclosporin; D020780:Matrix Metalloproteinase 9; D021984:Cyclophilin A