MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts.
MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of microRNAs by several mechanisms has been described in various disease states including cardiac disease. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK-MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.
Thum
Thomas
T
Department of Medicine I, Interdisziplinäres Zentrum für Klinische Forschung (IZKF), University of Wuerzburg, 97080 Wuerzburg, Germany.
Gross
Carina
C
Fiedler
Jan
J
Fischer
Thomas
T
Kissler
Stephan
S
Bussen
Markus
M
Galuppo
Paolo
P
Just
Steffen
S
Rottbauer
Wolfgang
W
Frantz
Stefan
S
Castoldi
Mirco
M
Soutschek
Jürgen
J
Koteliansky
Victor
V
Rosenwald
Andreas
A
Basson
M Albert
MA
Licht
Jonathan D
JD
Pena
John T R
JT
Rouhanifard
Sara H
SH
Muckenthaler
Martina U
MU
Tuschl
Thomas
T
Martin
Gail R
GR
Bauersachs
Johann
J
Engelhardt
Stefan
S
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051381:Rats
C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D048049:Extracellular Signal-Regulated MAP Kinases