TY - JOUR
T1 - MicroRNA Profiling Identifies MicroRNA-155 as an Adverse Mediator of Cardiac Injury and Dysfunction during Acute Viral MyoCarditis
AU - Corsten, M.F.
AU - Papageorgiou, A.
AU - Verhesen, W.
AU - Carai, P.
AU - Lindow, Morten
AU - Obad, S.
AU - Summer, G.
AU - Coort, S.L.M.
AU - Hazebroek, M.
AU - Van Leeuwen, R.
AU - Gijbels, M.J.J.
AU - Wijnands, E.
AU - Biessen, E.A.L.
AU - De Winther, M.P.J.
AU - Stassen, F.R.M.
AU - Carmeliet, P.
AU - Kauppinen, Sakari
AU - Schroen, B.
AU - Heymans, S.
PY - 2012/8/3
Y1 - 2012/8/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84864878194&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.112.267443
DO - 10.1161/CIRCRESAHA.112.267443
M3 - Journal article
AN - SCOPUS:84864878194
SN - 0009-7330
VL - 111
SP - 415
EP - 425
JO - Circulation Research
JF - Circulation Research
IS - 4
ER -