Journal
JCI INSIGHT
Volume 4, Issue 19, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.125507
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Funding
- NIH [S10 OD021724, S10 OD016234, NS047101, R01HL128630, HL128457]
- Swedish Hjart-Lungfonden [20180199]
- Knut and Alice Wallenberg Foundation
- Wallenberg Centre for Molecular and Translational Medicine
- Swedish Research Council [2016/82]
- Swedish Society [S150086]
- Ake Wiberg's Foundation [M15-0058]
- European Research Council [804418]
- European Research Council (ERC) [804418] Funding Source: European Research Council (ERC)
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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 Fox01 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.
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