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 October 3, 2019; First 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

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 4

miR-486 is sufficient to increase left ventricular growth and cardiomyocyte proliferation in neonatal mice.

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miR-486 is sufficient to increase left ventricular growth and cardiomyoc...
Echocardiograms were performed on neonatal mice 3 days after they were treated with miR-486 mimic or scramble control. (A) Representative M-mode echocardiography images of scramble BlockIT control– (CTL) or miR-486–treated neonatal mouse hearts used to calculate cardiac parameters (in B–G). (B) Fractional shortening (FS) was not changed between neonatal mice treated with either BlockIT (CTL) or miR-486. (C and D) LV internal dimension at the end of diastole (LVIDd; C) or in systole (LVIDs; D) were increased in the miR-486 mice by 16.9% (1.52 mm vs. 1.3 mm, **P < 0.01, as determined by t test) and 24.6% (0.71 mm vs. 0.57 mm; **P < 0.01, as determined by t test), respectively. (E and F) LV posterior wall thicknesses (LVPWd; E) and interventricular septal thicknesses (IVSd; F) during diastole were unchanged between BlockIT (CTL) and miR-486–treated neonatal mice. n = 7 control, n = 9 miR-486 treated. (G) End-diastolic diameter/posterior wall dimension (EDD/PWD) was increased by 20.7% in miR-486 mice (3.61 vs. 2.99, P < 0.005, as determined by t test). (H and I) Cardiomyocyte proliferation was quantified from cardiac sections of miR-486– or scramble control–treated (CTL-treated) mice using phospho-Histone H3 (highlighted by arrows; DAPI and F-actin/phalloidin as counterstain; H). Magnification of cardiac sections = ×20. Quantification of the ratio of positive phospho-Histone H3 (S10) versus DAPI-stained nuclei (I). miR-486 hearts exhibited a 2.48-fold increase in cardiomyocyte proliferation (**P < 0.01, as determined by t test, n = 3).