MicroRNA Profiling Identifies MicroRNA-155 as an Adverse Mediator of Cardiac Injury and Dysfunction during Acute Viral MyoCarditis

RATIONALE:: Viral myoCarditis results from an adverse immune response to Cardiotropic viruses, which Causes irreversible myo e destruction and heart failure in previously healthy people. The involvement of microRNAs and their usefulness as therapeutic targets in this process are unknown. OBJECTIVE:: To identify microRNAs involved in viral myoCarditis pathogenesis and susceptibility. METHODS AND RESULTS:: Cardiac 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 lympho es. Inhibition of microRNA-155 by a systemiCally delivered LNA-anti-miR attenuated Cardiac infiltration by mono e-macrophages, decreased T lympho e 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. CONCLUSIONS:: Our 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