miR-486 is modulated by stretch and increases ventricular growth

• Published in: JCI insight Vol. 4; no. 19
• Main Authors: Lange, Stephan, Banerjee, Indroneal, Carrion, Katrina, Serrano, Ricardo, Habich, Louisa, Kameny, Rebecca, Lengenfelder, Luisa, Dalton, Nancy, Meili, Rudolph, Börgeson, Emma, Peterson, Kirk, Ricci, Marco, Lincoln, Joy, Ghassemian, Majid, Fineman, Jeffery, Del Álamo, Juan C, Nigam, Vishal
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 12.09.2019
• Subjects: Animals; Animals, Newborn; aortic-valve; Biomechanical Phenomena; Cardiac and Cardiovascular Systems; cardiac-hypertrophy; Cell Proliferation - physiology; Cells, Cultured; congenital heart-disease; gene-expression; Heart Ventricles - growth & development; Heart Ventricles - metabolism; Humans; Hypoplastic Left Heart Syndrome - genetics; Hypoplastic Left Heart Syndrome - pathology; Hypoplastic Left Heart Syndrome - physiopathology; inhibition; Kardiologi; mechanical stretch; Mechanotransduction, Cellular - physiology; Mice; micrornas; MicroRNAs - metabolism; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; proliferation; Research & Experimental Medicine; serum response factor; Sheep; STAT1 Transcription Factor - metabolism; transcription factor; Cardiovascular disease; Cardiology; Noncoding RNAs; Proteomics; Cell Biology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.125507

Perturbations in biomechanical stimuli during cardiac development contribute to congenital cardiac defects such as hypoplastic left heart syndrome (HLHS). This study sought to identify stretch-responsive pathways involved in cardiac development. miRNA-Seq identified miR-486 as being increased in cardiomyocytes exposed to cyclic stretch in vitro. The right ventricles (RVs) of patients with HLHS experienced increased stretch and had a trend toward higher miR-486 levels. Sheep RVs dilated from excessive pulmonary blood flow had 60% more miR-486 compared with control RVs. The left ventricles of newborn mice treated with miR-486 mimic were 16.9%-24.6% larger and displayed a 2.48-fold increase in cardiomyocyte proliferation. miR-486 treatment decreased FoxO1 and Smad signaling while increasing the protein levels of Stat1. Stat1 associated with Gata-4 and serum response factor (Srf), 2 key cardiac transcription factors with protein levels that increase in response to miR-486. This is the first report to our knowledge of a stretch-responsive miRNA that increases the growth of the ventricle in vivo.