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

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

doi:10.1172/jci.insight.125507

Stephan Lange, Juan C Del Álamo + Show 15 more

Open Access

https://doi.org/10.1172/jci.insight.125507

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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.

Highlights

Biomechanical stretch stimuli are critically important in the heart, where ventricular cardiomyocytes are stretched every heartbeat during diastolic filling
We demonstrate that miR-486 is a stretch-responsive miRNA that is sufficient to increase ventricular growth, cardiomyocyte proliferation, and Stat1 levels in vivo. miR-486 is enriched in striated muscle [15,16,17] but little is known about its role in the heart
Given the small sample size (n = 3 for both groups), we focused on miRNAs that were changed with a P value of less than 0.1. miR-486 was the only miRNA that was modulated by stretch in the same direction in the hypoplastic left heart syndrome (HLHS) patient right ventricles (RVs) compared with control RV qPCR array data set, as the in vitro miRNA-Seq data of stretched versus static cardiomyocytes

Summary

Introduction

Biomechanical stretch stimuli are critically important in the heart, where ventricular cardiomyocytes are stretched every heartbeat during diastolic filling. Disruption of biomechanical stretch in utero can result in severe cardiac defects such as hypoplastic left heart syndrome (HLHS). While existing animal models [5,6,7,8,9,10,11] and computational studies [12] support the theory that HLHS results from perturbed biomechanical stimuli in utero, there is a paucity of data regarding molecular responses to biomechanical stretch. We demonstrate that miR-486 is a stretch-responsive miRNA that is sufficient to increase ventricular growth, cardiomyocyte proliferation, and Stat levels in vivo.

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