MicroRNA profiling identifies microRNA-155 as an adverse mediator of cardiac injury and dysfunction during acute viral myocarditis.
BACKGROUND
Viral 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.


OBJECTIVE
To identify microRNAs involved in viral myocarditis pathogenesis and susceptibility.


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 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.


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.
Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
Maarten F
MF
Corsten
Anna
A
Papageorgiou
Wouter
W
Verhesen
Paolo
P
Carai
Morten
M
Lindow
Susanna
S
Obad
Georg
G
Summer
Susan L M
SL
Coort
Mark
M
Hazebroek
Rick
R
van Leeuwen
Marion J J
MJ
Gijbels
Erwin
E
Wijnands
Erik A L
EA
Biessen
Menno P J
MP
De Winther
Frank R M
FR
Stassen
Peter
P
Carmeliet
Sakari
S
Kauppinen
Blanche
B
Schroen
Stephane
S
Heymans
D000818:Animals; D003384:Coxsackievirus Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy / Q000821:virology; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000472:pathogenicity; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009205:Myocarditis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy / Q000821:virology; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009841:Oligonucleotides / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D013997:Time Factors
C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D009841:Oligonucleotides; C477371:locked nucleic acid