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The prostacyclin agonist iloprost aggravates fibrosis and enhances viral replication in enteroviral myocarditis by modulation of ERK signaling and increase of iNOS expression

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Abstract

Enteroviruses, such as coxsackieviruses of group B (CVB), are able to induce a chronic inflammation of the myocardium, which may finally lead to the loss of functional tissue, remodeling processes and the development of fibrosis, thus affecting the proper contractile function of the heart. In other fibrotic diseases like scleroderma, the prostacyclin agonist iloprost was found to inhibit the extracellular signal-regulated kinase (ERK, p44/42 MAPK), a mitogen-activated protein kinase, and consecutively, the expression of the profibrotic cytokine connective tissue growth factor (CTGF), thereby preventing the development of fibrosis. As CTGF was found to mediate fibrosis in chronic CVB3 myocarditis as well, we evaluated whether the in vivo application of iloprost is capable to reduce the development of ERK/CTGF-mediated fibrosis in enteroviral myocarditis. Unexpectedly, the application of iloprost resulted in a prolonged myocardial inflammation and an aggravated fibrosis and failed to reduce activation of ERK and expression of CTGF at later stages of the disease. In addition, viral replication was found to be increased in iloprost-treated mice. Notably, the expression of cardiac inducible nitric oxide synthase (iNOS), which is known to aggravate myocardial damage in CVB3-infected mice, was strongly enhanced by iloprost. Using cultivated bone marrow macrophages (BMM), we confirmed these results, proving that iloprost potentiates the expression of iNOS mRNA and protein in CVB3-infected and IFN-gamma stimulated BMM. In conclusion, these results suggest a critical reflection of the clinical use of iloprost, especially in patients possibly suffering from an enteroviral myocarditis.

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Acknowledgments

We thank Sandra Bundschuh for excellent technical assistance. This work was supported by the DFG (SFB-TR19 TP Z4 to KK), and the BMBF (01EZ0817 to KK and RK) and the Interfakultäres Zentrum für Klinische Forschung (IZKF), University Hospital Tuebingen, Germany (to SG and KK).

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  1. Gudrun Szalay

    Present address: Paul Ehrlich Institute, Paul-Ehrlich-Str. 51-59, 63225, Langen, Germany

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  1. Department of Molecular Pathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstr 8, 72076, Tübingen, Germany

    Stefan Gruhle, Martina Sauter, Gudrun Szalay, Nicole Ettischer, Reinhard Kandolf & Karin Klingel

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Gruhle, S., Sauter, M., Szalay, G. et al. The prostacyclin agonist iloprost aggravates fibrosis and enhances viral replication in enteroviral myocarditis by modulation of ERK signaling and increase of iNOS expression. Basic Res Cardiol 107, 287 (2012). https://doi.org/10.1007/s00395-012-0287-z

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