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Published on: June 3, 2018
miR-1468-3p Promotes Aging-Related Cardiac Fibrosis
Ruizhu Lin1, Lea Rahtu-Korpela1, Johanna Magga2
1Research Unit of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Aapistie 5, 90220 Oulu, Finland.
Abstract:
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.
Insights
MicroRNAs (miRNAs) regulate gene expression and are involved in heart disease. This study identifies miR-1468-3p as a key regulator of cardiac fibrosis, promoting collagen deposition and cellular senescence. Targeting miR-1468-3p may offer therapeutic benefits for age-related cardiac fibrosis.
Area of Science:
- Cardiovascular Pathophysiology
- Molecular Biology
- Gene Regulation
Background:
- Non-coding microRNAs (miRNAs) are critical regulators of gene expression.
- Dysregulation of miRNAs contributes to cardiovascular diseases, including cardiac fibrosis.
- Identifying specific miRNAs involved in cardiac fibrosis is essential for therapeutic development.
Purpose of the Study:
- To identify microRNAs (miRNAs) that regulate cardiac fibrosis.
- To elucidate the role of miR-1468-3p in the development of primary myocardial fibrosis (PMF).
- To investigate the molecular mechanisms by which miR-1468-3p promotes cardiac fibrosis.
Main Methods:
- miRNA profiling of cardiac samples from control subjects and sudden cardiac death (SCD) victims with PMF.
- In vitro studies using human cardiac fibroblasts to assess the effects of miR-1468-3p.
- Mechanistic studies including RNA sequencing, dual-luciferase reporter assays, and Western blotting to identify target genes and signaling pathways.
Main Results:
- miR-1468-3p expression was increased in aged hearts with PMF and in aged control hearts.
- Augmenting miR-1468-3p in cardiac fibroblasts induced collagen deposition, increased metabolic activity, and promoted cellular senescence.
- miR-1468-3p was found to target dual-specificity phosphatases (DUSPs), particularly DUSP1, and enhance TGF-β1-p38 signaling, leading to collagen deposition.
Conclusions:
- miR-1468-3p promotes cardiac fibrosis by activating the TGF-β1-p38 signaling pathway.
- Targeting miR-1468-3p presents a potential therapeutic strategy to mitigate cardiac fibrosis, especially in the aging population.
- Understanding the role of miR-1468-3p in cardiac fibrosis opens new avenues for treating cardiovascular diseases.
