MicroRNA miR-425 is a negative regulator of atrial natriuretic peptide

Background

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that a genetic variant, rs5068 (A/G), is associated with blood pressure and the risk of hypertension. rs5068 lies in the 3’ untranslated region (3’UTR) of NPPA, the gene encoding atrial natriuretic peptide (ANP), and presence of the minor G allele is associated with increased circulating ANP levels and reduced blood pressure.

Results

We hypothesized the existence of a microRNA (miR) that targets the NPPA 3’UTR and that the binding of the miR to the NPPA 3’UTR would be disrupted in transcripts from the rs5068 minor allele. We identified a microRNA, miR-425, that is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 is expressed in human atria and ventricles. Using luciferase-3’UTR reporter constructs, we observed that miR-425 could silence reporter mRNAs carrying the NPPA major allele 3’UTR, but not those carrying the minor allele 3’UTR. Similarly, an anti-miR directed against miR-425 augmented expression of the luciferase-NPPA 3’UTR construct containing the major allele but not the minor allele. miR-425 reduced NPPA mRNA levels and ANP synthesis in human cardiomyocytes derived from induced pluripotent stem cells.

Conclusion

Our studies provide mechanistic insights into how a common genetic variant identified in population genetic studies can regulate ANP levels and blood pressure. miR-425 is a novel regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure.