Functional Screening Identifies MicroRNAs as Multi-Cellular Regulators of Heart Failure

• Published in: Scientific reports 2019-04, Vol.9 (1), p.6055, Article 6055
• Main Authors: Verjans, Robin, Derks, Wouter J. A., Korn, Kerstin, Sönnichsen, Birte, van Leeuwen, Rick E. W., Schroen, Blanche, van Bilsen, Marc, Heymans, Stephane
• Format: Article
• Language: English
• Subjects: 101/47; 13/109; 13/21; 14/56; 14/63; 38/1; 38/79; 42/109; 631/80/304; 692/4019/592/1540; 692/4019/592/75/230; Animals; Animals, Newborn; Cardiomegaly - genetics; Cardiomegaly - immunology; Cardiomegaly - pathology; Cardiomyocytes; Cell activation; Cells, Cultured; Chromosome 3; Collagen; Congestive heart failure; Coronary artery disease; Fibroblasts; Fibrosis; Gene Expression Profiling; Gene Expression Regulation; Heart failure; Heart Failure - genetics; Heart Failure - immunology; Heart Failure - pathology; Humanities and Social Sciences; Humans; Hypertrophy; Inflammation; Inflammatory diseases; Macrophage Activation - genetics; Macrophage Activation - immunology; Macrophages; Mice; MicroRNAs; MicroRNAs - metabolism; miRNA; multidisciplinary; Myocarditis - genetics; Myocarditis - immunology; Myocarditis - pathology; Myocardium - cytology; Myocardium - immunology; Myocardium - pathology; Myocytes, Cardiac; Polarization; Primary Cell Culture; Rats; Science; Science (multidisciplinary); Transcription
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-41491-9

Heart failure (HF) is the leading cause of death in the Western world. Pathophysiological processes underlying HF development, including cardiac hypertrophy, fibrosis and inflammation, are controlled by specific microRNAs (miRNAs). Whereas most studies investigate miRNA function in one particular cardiac cell type, their multicellular function is poorly investigated. The present study probed 194 miRNAs –differentially expressed in cardiac inflammatory disease – for regulating cardiomyocyte size, cardiac fibroblasts collagen content, and macrophage polarization. Of the tested miRNAs, 13%, 26%, and 41% modulated cardiomyocyte size, fibroblast collagen production, and macrophage polarization, respectively. Seventeen miRNAs affected all three cellular processes, including miRNAs with established (miR-210) and unknown roles in cardiac pathophysiology (miR-145-3p). These miRNAs with a multi-cellular function commonly target various genes. In-depth analysis in vitro of previously unstudied miRNAs revealed that the observed phenotypical alterations concurred with changes in transcript and protein levels of hypertrophy-, fibrosis- and inflammation-related genes. MiR-145-3p and miR-891a-3p were identified to regulate the fibrotic response, whereas miR-223-3p, miR-486-3p, and miR-488-5p modulated macrophage activation and polarisation. In conclusion, miRNAs are multi-cellular regulators of different cellular processes underlying cardiac disease. We identified previously undescribed roles of miRNAs in hypertrophy, fibrosis, and inflammation, and attribute new cellular effects to various well-known miRNAs.