Novel microRNA regulators of atrial natriuretic peptide production

Connie Wu, Pankaj Arora, Obiajulu Agha, Liam A. Hurst, Kaitlin Allen, Daniel I. Nathan, Dongjian Hu, Pawina Jiramongkolchai, J. Gustav Smith, Olle Melander, Sander Trenson, Stefan P. Janssens, Ibrahim Domian, Thomas J. Wang, Kenneth D. Bloch, Emmanuel S. Buys, Donald B. Bloch, Christopher Newton-Cheh

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure.

Original languageEnglish (US)
Pages (from-to)1977-1987
Number of pages11
JournalMolecular and cellular biology
Volume36
Issue number14
DOIs
StatePublished - 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Wu, C., Arora, P., Agha, O., Hurst, L. A., Allen, K., Nathan, D. I., Hu, D., Jiramongkolchai, P., Smith, J. G., Melander, O., Trenson, S., Janssens, S. P., Domian, I., Wang, T. J., Bloch, K. D., Buys, E. S., Bloch, D. B., & Newton-Cheh, C. (2016). Novel microRNA regulators of atrial natriuretic peptide production. Molecular and cellular biology, 36(14), 1977-1987. https://doi.org/10.1128/MCB.01114-15