Deficiency of MicroRNA miR-1954 Promotes Cardiac Remodeling and Fibrosis

• Published in: Journal of the American Heart Association Vol. 8; no. 21; p. e012880
• Main Authors: Chiasson, Valorie, Takano, Ana Paula Cremasco, Guleria, Rakeshwar S, Gupta, Sudhiranjan
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 05.11.2019; Wiley
• Subjects: Actins - metabolism; Angiotensin II - pharmacology; Animals; bcl-2 Homologous Antagonist-Killer Protein - metabolism; cardiac remodeling; Cardiomegaly - genetics; Cardiomegaly - therapy; Caspase 3 - metabolism; Collagen Type I - metabolism; Collagen Type I, alpha 1 Chain; Collagen Type III - metabolism; Collagen Type IV - metabolism; Connective Tissue Growth Factor - metabolism; Disease Models, Animal; fibrosis; Fibrosis - genetics; Fibrosis - therapy; High-Throughput Nucleotide Sequencing; Interleukin-6 - metabolism; Mice, Transgenic; microRNA; MicroRNAs - genetics; Myocardium - pathology; Organ Size; Original Research; S100 Calcium-Binding Protein A4 - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Thrombospondin 1 - metabolism; Transforming Growth Factor beta1 - metabolism; transgenic mice; Up-Regulation; Ventricular Remodeling - genetics; microRNA; fibrosis; transgenic mice; cardiac remodeling
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.119.012880

Background Cardiac fibrosis occurs because of disruption of the extracellular matrix network leading to myocardial dysfunction. Angiotensin II (AngII) has been implicated in the development of cardiac fibrosis. Recently, microRNAs have been identified as an attractive target for therapeutic intervention in cardiac pathologies; however, the underlying mechanism of microRNAs in cardiac fibrosis remains unclear. Next-generation sequencing analysis identified a novel characterized microRNA, miR-1954, that was significantly reduced in AngII-infused mice. The finding led us to hypothesize that deficiency of miR-1954 triggers cardiac fibrosis. Methods and Results A transgenic mouse was created using α-MHC (α-myosin heavy chain) promoter and was challenged with AngII infusion. AngII induced cardiac hypertrophy and remodeling. The in vivo overexpression of miR-1954 showed significant reduction in cardiac mass and blood pressure in AngII-infused mice. Further analysis showed significant reduction in cardiac fibrotic genes, hypertrophy marker genes, and an inflammatory gene and restoration of a calcium-regulated gene (Atp2a2 [ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2]; also known as SERCA2), but no changes were observed in apoptotic genes. THBS1 (thrombospondin 1) is indicated as a target gene for miR-1954. Conclusions Our findings provide evidence, for the first time, that miR-1954 plays a critical role in cardiac fibrosis by targeting THBS1. We conclude that promoting the level of miR-1954 would be a promising strategy for the treatment of cardiac fibrosis.