Inhibition of miR-25 Improves Cardiac Contractility in the Failing Heart

Heart failure is characterized by a debilitating decline in cardiac function(1), and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy(2,3). microRNAs (miRs) are dysregulated with heart failure(4,5) but whether they control contractility or constitute therapeutic targets remain speculative. Using high throughput, functional screening of the human microRNAome, we identified miRs that suppress intracellular calcium handling in heart muscle by interacting with mRNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a. Of 875 miRs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas AAV9-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 dramatically halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggests that it might be targeted therapeutically to restore function.