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Antisense regulation of atrial natriuretic peptide expression

Celik, Selvi LU ; Karbalaei Sadegh, Mardjaneh LU ; Morley, Michael ; Roselli, Carolina ; Ellinor, Patrick T ; Cappola, Thomas P ; Smith, J. Gustav LU and Gidlöf, Olof LU (2019) In JCI Insight 4(19).
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
JCI Insight
volume
4
issue
19
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:85072983185
ISSN
2379-3708
DOI
10.1172/jci.insight.130978
language
English
LU publication?
yes
id
3e98045f-a6f0-4e47-8d65-a49af1d4922f
date added to LUP
2021-03-09 10:17:57
date last changed
2022-04-27 00:38:07
@article{3e98045f-a6f0-4e47-8d65-a49af1d4922f,
  abstract     = {{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.}},
  author       = {{Celik, Selvi and Karbalaei Sadegh, Mardjaneh and Morley, Michael and Roselli, Carolina and Ellinor, Patrick T and Cappola, Thomas P and Smith, J. Gustav and Gidlöf, Olof}},
  issn         = {{2379-3708}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{19}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{JCI Insight}},
  title        = {{Antisense regulation of atrial natriuretic peptide expression}},
  url          = {{http://dx.doi.org/10.1172/jci.insight.130978}},
  doi          = {{10.1172/jci.insight.130978}},
  volume       = {{4}},
  year         = {{2019}},
}