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 su...

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Bibliographic Details
Published in:PloS one 2020-02, Vol.15 (2), p.e0229409
Main Authors: Connolly, Martin, Garfield, Benjamin E, Crosby, Alexi, Morrell, Nick W, Wort, Stephen J, Kemp, Paul R, Martelli, Fabio
Format: Article
Language:English
Subjects:
Angiotensin II
Bone morphogenetic proteins
Fluorescence
Heart
Heart hypertrophy
Hypertension
Hypertrophy
MicroRNA
Pulmonary hypertension
Transforming growth factors
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0229409