MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts

Abstract

MicroRNAs, the small noncoding RNAs that regulate gene expression, have been shown to be expressed in cardiac muscle cells and their aberrant regulation was correlated with heart disease. Thum et al. have looked at how microRNAs in other heart cells may contribute to disease. They find that microRNA-21 (miR-21) is upregulated in cardiac fibroblasts in mouse models of heart disease. This activates a signalling pathway that exacerbates the extent of damage to the heart tissues. When miR-21 is silenced in vivo using a specific antisense oligonucleotide (an anti-miR-21 antagomir), heart failure can be prevented. In addition, giving mice anti-miR-21 after established heart failure appeared to reverse some of the tissue damage. This work validates miR-21 as a disease target in heart failure and illustrates the broad therapeutic potential of microRNA modulation. MicroRNAs are expressed in a type of heart cell known as cardiomyocytes and their aberrant regulation was correlated with heart disease. This study looks at how miRNAs in other heart cells may contribute to disease. It is found that in cardiac fibroblasts, miR-21 is upregulated in diseased heart. This activates a signalling pathway that exacerbates cardiac disease. By using an RNA molecule directed against miR-21, it was possible to reverse these effects, demonstrating that therapeutic treatment to downregulate a microRNA can be effective in vivo. MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs1,2. Dysregulation of microRNAs by several mechanisms has been described in various disease states3,4,5 including cardiac disease6,7,8,9,10. 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.