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Olof Gidlöf

Research project participant

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Antisense regulation of atrial natriuretic peptide expression

Author

  • Selvi Celik
  • Mardjaneh Karbalaei Sadegh
  • Michael Morley
  • Carolina Roselli
  • Patrick T Ellinor
  • Thomas P Cappola
  • J. Gustav Smith
  • Olof Gidlöf

Summary, in English

The cardiac hormone atrial natriuretic peptide (ANP) is a central regulator of blood volume and a therapeutic target in hypertension and heart failure. Enhanced ANP activity in such conditions through inhibition of the degradative enzyme neprilysin has shown clinical efficacy but is complicated by consequences of simultaneous accumulation of a heterogeneous array of other hormones. Targets for specific ANP enhancement have not been available. Here, we describe a cis-acting antisense transcript (NPPA-AS1), which negatively regulates ANP expression in human cardiomyocytes. We show that NPPA-AS1 regulates ANP expression via facilitating NPPA repressor RE1-silencing transcription factor (REST) binding to its promoter, rather than forming an RNA duplex with ANP mRNA. Expression of ANP mRNA and NPPA-AS1 was increased and correlated in isolated strained human cardiomyocytes and in hearts from patients with advanced heart failure. Further, inhibition of NPPA-AS1 in vitro and in vivo resulted in increased myocardial expression of ANP, increased circulating ANP, increased renal cGMP, and lower blood pressure. The effects of NPPA-AS1 inhibition on NPPA expression in human cardiomyocytes were further marked under cell-strain conditions. Collectively, these results implicate the antisense transcript NPPA-AS1 as part of a physiologic self-regulatory ANP circuit and a viable target for specific ANP augmentation.

Department/s

  • Molecular Epidemiology and Cardiology
  • Cardiovascular Epigenetics
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • WCMM-Wallenberg Centre for Molecular Medicine
  • Cardiology
  • Heart Failure and Mechanical Support
  • EpiHealth: Epidemiology for Health
  • Molecular Cardiology

Publishing year

2019-10-03

Language

English

Publication/Series

JCI Insight

Volume

4

Issue

19

Document type

Journal article

Publisher

The American Society for Clinical Investigation

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Molecular Epidemiology and Cardiology
  • Cardiovascular Epigenetics
  • Heart Failure and Mechanical Support
  • Molecular Cardiology

ISBN/ISSN/Other

  • ISSN: 2379-3708