miR-1468-3p Promotes Aging-Related Cardiac Fibrosis.

Autor:	Lin R; Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland., Rahtu-Korpela L; Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland., Magga J; Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland., Ulvila J; Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland., Swan J; Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland., Kemppi A; Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland., Pakanen L; Department of Forensic Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland; Forensic Medicine Unit, National Institute for Health and Welfare, Aapistie 5, 90220 Oulu, Finland., Porvari K; Department of Forensic Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland., Huikuri H; Division of Cardiology, Research Unit of Internal Medicine, University of Oulu and Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland; Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Aapistie 5, 90220 Oulu, Finland., Junttila J; Biocenter Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland; Division of Cardiology, Research Unit of Internal Medicine, University of Oulu and Oulu University Hospital, Kajaanintie 50, 90220 Oulu, Finland; Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Aapistie 5, 90220 Oulu, Finland., Kerkelä R; Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland; Biocenter Oulu, University of Oulu, Aapistie 5, 90220 Oulu, Finland; Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, Aapistie 5, 90220 Oulu, Finland. Electronic address: risto.kerkela@oulu.fi.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2020 Jun 05; Vol. 20, pp. 589-605. Date of Electronic Publication: 2020 Apr 08.
DOI:	10.1016/j.omtn.2020.04.001
Abstrakt:	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. (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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