• Maarten F Corsten, Anna Papageorgiou, Wouter Verhesen, Paolo Carai, Morten Lindow, Susanna Obad, Georg Summer, Susan L M Coort, Mark Hazebroek, Rick van Leeuwen, Marion J J Gijbels, Erwin Wijnands, Erik A L Biessen, Menno P J De Winther, Frank R M Stassen, Peter Carmeliet, Sakari Kauppinen, Blanche Schroen, and Stephane Heymans.
• Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
• Circ. Res. 2012 Aug 3; 111 (4): 415-25.

RationaleViral myocarditis results from an adverse immune response to cardiotropic viruses, which causes irreversible myocyte destruction and heart failure in previously healthy people. The involvement of microRNAs and their usefulness as therapeutic targets in this process are unknown.ObjectiveTo identify microRNAs involved in viral myocarditis pathogenesis and susceptibility.Methods And ResultsCardiac microRNAs were profiled in both human myocarditis and in Coxsackievirus B3-injected mice, comparing myocarditis-susceptible with nonsusceptible mouse strains longitudinally. MicroRNA responses diverged depending on the susceptibility to myocarditis after viral infection in mice. MicroRNA-155, -146b, and -21 were consistently and strongly upregulated during acute myocarditis in both humans and susceptible mice. We found that microRNA-155 expression during myocarditis was localized primarily in infiltrating macrophages and T lymphocytes. Inhibition of microRNA-155 by a systemically delivered LNA-anti-miR attenuated cardiac infiltration by monocyte-macrophages, decreased T lymphocyte activation, and reduced myocardial damage during acute myocarditis in mice. These changes were accompanied by the derepression of the direct microRNA-155 target PU.1 in cardiac inflammatory cells. Beyond the acute phase, microRNA-155 inhibition reduced mortality and improved cardiac function during 7 weeks of follow-up.ConclusionsOur data show that cardiac microRNA dysregulation is a characteristic of both human and mouse viral myocarditis. The inflammatory microRNA-155 is upregulated during acute myocarditis, contributes to the adverse inflammatory response to viral infection of the heart, and is a potential therapeutic target for viral myocarditis.

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