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Functional Screening Identifies MicroRNA Regulators of Corin Activity and Atrial Natriuretic Peptide Biogenesis

Celik, Selvi LU ; Karbalaei-Sadegh, Mardjaneh LU ; Rådegran, Göran LU ; Smith, J. Gustav LU and Gidlöf, Olof LU (2019) In Molecular and Cellular Biology 39(23).
Abstract

Atrial natriuretic peptide (ANP) represents an attractive therapeutic target in hypertension and heart failure. The biologically active form of ANP is produced by the cardiac serine protease corin, and modulation of its activity might therefore represent a novel approach for ANP augmentation. MicroRNAs (miRNAs) are pervasive regulators of gene expression, but their potential role in regulating corin activity has not been elucidated. Our aim was to systematically identify and characterize miRNA regulators of corin activity in human cardiomyocytes. An assay for measuring serine protease activity in human induced pluripotent stem cell (iPS)-derived cardiomyocytes was used to perform a comprehensive screening of miRNA family inhibitors (n =... (More)

Atrial natriuretic peptide (ANP) represents an attractive therapeutic target in hypertension and heart failure. The biologically active form of ANP is produced by the cardiac serine protease corin, and modulation of its activity might therefore represent a novel approach for ANP augmentation. MicroRNAs (miRNAs) are pervasive regulators of gene expression, but their potential role in regulating corin activity has not been elucidated. Our aim was to systematically identify and characterize miRNA regulators of corin activity in human cardiomyocytes. An assay for measuring serine protease activity in human induced pluripotent stem cell (iPS)-derived cardiomyocytes was used to perform a comprehensive screening of miRNA family inhibitors (n = 42). miRNA 1-3p (miR-1-3p) was identified as a potent inhibitor of corin activity. The interaction between miR-1-3p and a specific target site in the CORIN 3' untranslated region (3' UTR) was confirmed through argonaute 2 (AGO2)-RNA immunoprecipitation and reporter assays. Inhibition of miR-1-3p resulted in upregulation of CORIN gene and protein expression, as well as a concomitant increase in extracellular ANP. Additionally, miR-1-3p was found to interact with and inhibit the expression of several transcriptional activators of ANP gene expression. In conclusion, we have identified a novel regulator of corin activity and ANP biogenesis in human cardiomyocytes that might be of potential future therapeutic utility.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
atrial natriuretic peptide, cardiomyocyte, corin, heart failure, microRNA
in
Molecular and Cellular Biology
volume
39
issue
23
article number
e00271-19
publisher
American Society for Microbiology
external identifiers
  • scopus:85074965563
  • pmid:31548261
ISSN
0270-7306
DOI
10.1128/MCB.00271-19
language
English
LU publication?
yes
id
34e33498-4a60-4b33-95e7-6ca9b4f33955
date added to LUP
2019-11-28 12:33:19
date last changed
2024-06-12 05:15:40
@article{34e33498-4a60-4b33-95e7-6ca9b4f33955,
  abstract     = {{<p>Atrial natriuretic peptide (ANP) represents an attractive therapeutic target in hypertension and heart failure. The biologically active form of ANP is produced by the cardiac serine protease corin, and modulation of its activity might therefore represent a novel approach for ANP augmentation. MicroRNAs (miRNAs) are pervasive regulators of gene expression, but their potential role in regulating corin activity has not been elucidated. Our aim was to systematically identify and characterize miRNA regulators of corin activity in human cardiomyocytes. An assay for measuring serine protease activity in human induced pluripotent stem cell (iPS)-derived cardiomyocytes was used to perform a comprehensive screening of miRNA family inhibitors (n = 42). miRNA 1-3p (miR-1-3p) was identified as a potent inhibitor of corin activity. The interaction between miR-1-3p and a specific target site in the CORIN 3' untranslated region (3' UTR) was confirmed through argonaute 2 (AGO2)-RNA immunoprecipitation and reporter assays. Inhibition of miR-1-3p resulted in upregulation of CORIN gene and protein expression, as well as a concomitant increase in extracellular ANP. Additionally, miR-1-3p was found to interact with and inhibit the expression of several transcriptional activators of ANP gene expression. In conclusion, we have identified a novel regulator of corin activity and ANP biogenesis in human cardiomyocytes that might be of potential future therapeutic utility.</p>}},
  author       = {{Celik, Selvi and Karbalaei-Sadegh, Mardjaneh and Rådegran, Göran and Smith, J. Gustav and Gidlöf, Olof}},
  issn         = {{0270-7306}},
  keywords     = {{atrial natriuretic peptide; cardiomyocyte; corin; heart failure; microRNA}},
  language     = {{eng}},
  number       = {{23}},
  publisher    = {{American Society for Microbiology}},
  series       = {{Molecular and Cellular Biology}},
  title        = {{Functional Screening Identifies MicroRNA Regulators of Corin Activity and Atrial Natriuretic Peptide Biogenesis}},
  url          = {{http://dx.doi.org/10.1128/MCB.00271-19}},
  doi          = {{10.1128/MCB.00271-19}},
  volume       = {{39}},
  year         = {{2019}},
}