University of Oulu

Ruizhu Lin, Lea Rahtu-Korpela, Johanna Magga, Johanna Ulvila, Julia Swan, Anna Kemppi, Lasse Pakanen, Katja Porvari, Heikki Huikuri, Juhani Junttila, Risto Kerkelä, miR-1468-3p Promotes Aging-Related Cardiac Fibrosis, Molecular Therapy - Nucleic Acids, Volume 20, 2020, Pages 589-605, ISSN 2162-2531,

miR-1468-3p promotes aging–related cardiac fibrosis

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Author: Lin, Ruizhu1; Rahtu-Korpela, Lea1; Magga, Johanna1,2;
Organizations: 1Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland
2Biocenter Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland
3Department of Forensic Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland
4Forensic Medicine Unit, National Institute for Health and Welfare, Aapistie 5, 90220 Oulu, Finland
5Division of Cardiology, Research Unit of Internal Medicine, University of Oulu and Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland
6Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Aapistie 5, 90220 Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.2 MB)
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Language: English
Published: Elsevier, 2020
Publish Date: 2020-07-06


Non-coding microRNAs (miRNAs) are powerful regulators of gene expression and critically involved in cardiovascular pathophysiology. The aim of the current study was to identify miRNAs regulating cardiac fibrosis. Cardiac samples of age-matched control subjects and sudden cardiac death (SCD) victims with primary myocardial fibrosis (PMF) were subjected to miRNA profiling. Old SCD victims with PMF and healthy aged human hearts showed increased expression of miR-1468-3p. In vitro studies in human cardiac fibroblasts showed that augmenting miR-1468-3p levels induces collagen deposition and cell metabolic activity and enhances collagen 1, connective tissue growth factor, and periostin expression. In addition, miR-1468-3p promotes cellular senescence with increased senescence-associated β-galactosidase activity and increased expression of p53 and p16. AntimiR-1468-3p antagonized transforming growth factor β1 (TGF-β1)-induced collagen deposition and metabolic activity. Mechanistically, mimic-1468-3p enhanced p38 phosphorylation, while antimiR-1468-3p decreased TGF-β1-induced p38 activation and abolished p38-induced collagen deposition. RNA sequencing analysis, a computational prediction model, and qPCR analysis identified dual-specificity phosphatases (DUSPs) as miR-1468-3p target genes, and regulation of DUSP1 by miR-1468-3p was confirmed with a dual-luciferase reporter assay. In conclusion, miR-1468-3p promotes cardiac fibrosis by enhancing TGF-β1-p38 signaling. Targeting miR-1468-3p in the older population may be of therapeutic interest to reduce cardiac fibrosis.

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Series: Molecular therapy. Nucleic acids
ISSN: 2162-2531
ISSN-E: 2162-2531
ISSN-L: 2162-2531
Volume: 20
Pages: 589 - 605
DOI: 10.1016/j.omtn.2020.04.001
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1182 Biochemistry, cell and molecular biology
3121 General medicine, internal medicine and other clinical medicine
Funding: This work was supported by the Academy of Finland (grants 131020 and 297094 to R.K. and 268505 to J.M.), the Finnish Foundation for Cardiovascular Research (to L.R.-K., J.M., H.H., and R.K.), and by the Jane and Aatos Erkko Foundation (to R.K., H.H., and J.J.).
Academy of Finland Grant Number: 131020
Detailed Information: 131020 (Academy of Finland Funding decision)
297094 (Academy of Finland Funding decision)
268505 (Academy of Finland Funding decision)
Copyright information: © 2020 The Author(s). This is an open access article under the CC BY-NC-ND license (