P97MicroRNA-155 mediates cardiac inflammation and injury in acute viral myocarditis

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Abstract

Backgroud

Viral myocarditis (VM) is the most prevalent cause of heart failure in young adults. The pathogenesis is based on an adverse immune response inflicting irreversible damage to the myocardium. In this study, we examined the role of inflammatory microRNAs – and microRNA-155 in particular – in VM.

Methods and Results

Cardiac microRNAs were profiled in both human myocarditis and in Coxsackievirus B3-injected mice, comparing myocarditis-susceptible to non-susceptible 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 up-regulated during acute myocarditis in both humans and susceptible mice. In situ hybridization revealed that microRNA-155 expression during myocarditis was localized primarily in infiltrating inflammatory cells. Inhibition of miR-155 in C3H mice by a systemically delivered LNA-antimiR suppressed CVB3-induction of miR-155 in the heart (75% reduction, p < 0.001) and attenuated cardiac inflammation and necrosis (LV necrotic area: LNA-control: 35.3% versus LNA-antimiR-155 19.7%, p < 0.01, n=11 and 12, respectively) during acute myocarditis. MicroRNA-155 inhibition did not affect viral load before onset of inflammation, but decreased viral copy numbers during the inflammatory phase 7 days after infection (4-fold, p < 0.01), indicating that microRNA-155 loss-of-function did not compromise viral clearance while preventing adverse cardiac inflammation.

Conclusions

MicroRNA-155 is selectively upregulated in inflammatory cells during acute viral myocarditis and is a mediator of adverse cardiac inflammation after CVB3 infection in mice. Its knockdown attenuates myocardial inflammation and necrosis without compromising viral clearance. Our data identify microRNA-155 as a potential therapeutic target in the treatment of viral myocarditis.

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