MiR-1-5p targets TGF-beta R1 and is suppressed in the hypertrophying hearts of rats with pulmonary arterial hypertension

The microRNA miR-1 is an important regulator of muscle phenotype including cardiac muscle. Down-regulation of miR-1 has been shown to occur in left ventricular hypertrophy but its contribution to right ventricular hypertrophy in pulmonary arterial hypertension are not known. Previous studies have suggested that miR-1 may suppress transforming growth factor-beta (TGF-beta) signalling, an important pro-hypertrophic pathway but only indirect mechanisms of regulation have been identified. We identified the TGF-beta type 1 receptor (TGF beta R1) as a putative miR-1 target. We therefore hypothesized that miR-1 and TGF-beta R1 expression would be inversely correlated in hypertrophying right ventricle of rats with pulmonary arterial hypertension and that miR-1 would inhibit TGF-beta signalling by targeting TGF beta R1 expression. Quantification of miR-1 and TGF-beta R1 in rats treated with monocrotaline to induce pulmonary arterial hypertension showed appropriate changes in miR-1 and TGF-beta R1 expression in the hypertrophying right ventricle. A miR-1-mimic reduced enhanced green fluorescent protein expression from a reporter vector containing the TGF-beta R1 3'-untranslated region and knocked down endogenous TGF-beta R1. Lastly, miR-1 reduced TGF beta activation of a (mothers against decapentaplegic homolog) SMAD2/3-dependent reporter. Taken together, these data suggest that miR-1 targets TGF-beta R1 and reduces TGF-beta signalling, so a reduction in miR-1 expression may increase TGF-beta signalling and contribute to cardiac hypertrophy.