ß-arrestin-biased agonism of ß-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling.
J Mol Cell Cardiol
; 118: 225-236, 2018 05.
Article
em En
| MEDLINE
| ID: mdl-29627294
ABSTRACT
RATIONALE MicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate target genes. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed by Drosha into premature miRs (pre-miRs) and further cleaved by Dicer into mature miRs. Initially discovered to desensitize ß-adrenergic receptor (ßAR) signaling, ß-arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the ß-arrestin-biased ßAR ligand carvedilol, we previously showed that ß-arrestin1 (not ß-arrestin2)-biased ß1AR (not ß2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes ß-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1. OBJECTIVE:
Here, we investigate whether ß-arrestin-mediated ßAR signaling induced by carvedilol could regulate Dicer-mediated miR maturation in the cytoplasm and whether this novel mechanism promotes cardioprotective signaling. METHODS ANDRESULTS:
In mouse hearts, carvedilol indeed upregulates three mature miRs, but not their pre-miRs and pri-miRs, in a ß-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on ß2ARs and ß1ARs, respectively. Mechanistically, ß-arrestin 1 or 2 regulates maturation of three newly identified ßAR/ß-arrestin-responsive miRs (ß-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of ß-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, ß-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets.CONCLUSIONS:
Our findings indicate a novel role for ßAR-mediated ß-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cardiotônicos
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Transdução de Sinais
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Receptores Adrenérgicos beta
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Agonistas Adrenérgicos beta
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MicroRNAs
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Ribonuclease III
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Beta-Arrestinas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Mol Cell Cardiol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos