β-arrestin1-biased β1-adrenergic receptor signaling regulates MicroRNA processing

Il-man Kim, Yongchao Wang, Kyoung Mi Park, Yaoping Tang, Jian Peng Teoh, Joseph Vinson, Christopher J. Traynham, Gianluigi Pironti, Lan Mao, Huabo Su, John A Johnson, Walter J. Koch, Howard A. Rockman

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

RATIONALE:: MicroRNAs (miRs) are small, noncoding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary miR transcripts (pri-miRs), they are enzymatically processed in the nucleus by Drosha into hairpin intermediate miRs (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes after activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-arrestins are now appreciated to transduce multiple effector pathways independent of G-protein-mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the β-arrestin-biased βAR agonist, carvedilol, activates cellular pathways in the heart. OBJECTIVE:: Here, we tested whether carvedilol could activate β-arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects. METHODS AND RESULTS:: In human cells and mouse hearts, carvedilol upregulates a subset of mature and pre-miRs, but not their pri-miRs, in β1AR-, G-protein-coupled receptor kinase 5/6-, and β-arrestin1-dependent manner. Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1 and Drosha on pri-miRs. CONCLUSIONS:: Our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling activated by carvedilol in miR biogenesis, which may be linked, in part, to its mechanism for cell survival.

Original languageEnglish (US)
Pages (from-to)833-844
Number of pages12
JournalCirculation research
Volume114
Issue number5
DOIs
StatePublished - Feb 28 2014

Keywords

  • Carvedilol
  • heart diseases

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Kim, I., Wang, Y., Park, K. M., Tang, Y., Teoh, J. P., Vinson, J., Traynham, C. J., Pironti, G., Mao, L., Su, H., Johnson, J. A., Koch, W. J., & Rockman, H. A. (2014). β-arrestin1-biased β1-adrenergic receptor signaling regulates MicroRNA processing. Circulation research, 114(5), 833-844. https://doi.org/10.1161/CIRCRESAHA.114.302766