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miR-486 is modulated by stretch and increases ventricular growth
Stephan Lange, … , Juan C. del Álamo, Vishal Nigam
Stephan Lange, … , Juan C. del Álamo, Vishal Nigam
Published September 12, 2019
Citation Information: JCI Insight. 2019;4(19):e125507. https://doi.org/10.1172/jci.insight.125507.
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Research Article Cardiology Cell biology

miR-486 is modulated by stretch and increases ventricular growth

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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.

Authors

Stephan Lange, Indroneal Banerjee, Katrina Carrion, Ricardo Serrano, Louisa Habich, Rebecca Kameny, Luisa Lengenfelder, Nancy Dalton, Rudolph Meili, Emma Börgeson, Kirk Peterson, Marco Ricci, Joy Lincoln, Majid Ghassemian, Jeffery Fineman, Juan C. del Álamo, Vishal Nigam

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Figure 6

miR-486 modulates Stat1 levels by targeting Tgf-β/Smad signaling.

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miR-486 modulates Stat1 levels by targeting Tgf-β/Smad signaling.
(A and...
(A and B) Cardiomyocytes transfected with miR-486 have significantly less Smad2 (0.71 ± 0.08, n = 3, P = 0.036, as determined by t test) and Smad3 levels (0.69 ± 0.06121, n = 3, P = 0.044, as determined by t test), as compared with scrambled controls (BlockIT). Smad levels were normalized to actin. (C) The TGF-β2–treated cells have 53.3% less (corresponding to average control cQ = 0.22 vs. average TGF-β2–treated EMCM cQ = 1.32) miR-486, as compared with untreated cells exposed to cyclic stretch (P < 0.05, as determined by t test). (D and E) Cardiomyocytes treated with TGF-β2 have significantly decreased p-Stat1 S727 levels (0.44 ± 0.06, n = 3, P = 0.0099, as determined by t test) as compared with untreated controls (BlockIT). Total Stat1 levels were not significantly changed (0.87 ± 0.08, n = 3, P = 0.4347, as determined by t test). Stat1 and p-Stat1 levels were normalized to actin. *P < 0.05, **P < 0.01 vs. control.

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