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.