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Olle Melander

Principal investigator

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Novel microRNA regulators of atrial natriuretic peptide production

Author

  • Connie Wu
  • Pankaj Arora
  • Obiajulu Agha
  • Liam A. Hurst
  • Kaitlin Allen
  • Daniel I. Nathan
  • Dongjian Hu
  • Pawina Jiramongkolchai
  • 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

Summary, in English

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.

Department/s

  • Molecular Epidemiology and Cardiology
  • Cardiovascular Research - Hypertension
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • EpiHealth: Epidemiology for Health

Publishing year

2016

Language

English

Pages

1977-1987

Publication/Series

Molecular and Cellular Biology

Volume

36

Issue

14

Document type

Journal article

Publisher

American Society for Microbiology

Topic

  • Cell and Molecular Biology
  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Molecular Epidemiology and Cardiology
  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 0270-7306