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JCI Insight. 2019 Sep 12;4(19). pii: 125507. doi: 10.1172/jci.insight.125507.

miR-486 is modulated by stretch and increases ventricular growth.

Author information

1
Division of Cardiovascular Medicine, Department of Medicine, UCSD School of Medicine, San Diego, California, USA.
2
Institute of Medicine, Department of Molecular and Clinical Medicine, the Wallenberg Laboratory and Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
3
Division of Cardiology, Department of Pediatrics, UCSD School of Medicine, San Diego, California, USA.
4
Department of Mechanical and Aerospace Engineering, UCSD, San Diego, USA.
5
Department of Pediatrics, UCSF School of Medicine, San Francisco, USA.
6
Division of Cardiothoracic Surgery and.
7
Division of Pediatric Surgery, Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
8
Center for Cardiovascular Research, Nationwide Children's Hospital, Columbus, Ohio, USA.
9
Department of Chemistry and Biochemistry, UCSD, San Diego, USA.
10
Division of Cardiology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA.
11
Seattle Children's Research Institute, Seattle, Washington, USA.

Abstract

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.

KEYWORDS:

Cardiology; Cardiovascular disease; Cell Biology; Noncoding RNAs; Proteomics

PMID:
31513548
DOI:
10.1172/jci.insight.125507
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