Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts

AimsAnimal models have been used to show that there are critical molecular mechanisms that can be activated to induce myocardial repair at specific times in development. For example, specific miRNAs are critical for regulating the response to myocardial infarction (MI) and improving the response to...

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Main Authors: Mitchell C. Lock, Ross L. Tellam, Jack R. T. Darby, Jia Yin Soo, Doug A. Brooks, Mike Seed, Joseph B. Selvanayagam, Janna L. Morrison
Format: Article
Language:English
Published: Frontiers Media S.A. 2020-06-01
Series:Frontiers in Physiology
Subjects:
Online Access:https://www.frontiersin.org/article/10.3389/fphys.2020.00614/full
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author Mitchell C. Lock
Ross L. Tellam
Jack R. T. Darby
Jia Yin Soo
Doug A. Brooks
Doug A. Brooks
Mike Seed
Joseph B. Selvanayagam
Janna L. Morrison
author_facet Mitchell C. Lock
Ross L. Tellam
Jack R. T. Darby
Jia Yin Soo
Doug A. Brooks
Doug A. Brooks
Mike Seed
Joseph B. Selvanayagam
Janna L. Morrison
author_sort Mitchell C. Lock
collection DOAJ
description AimsAnimal models have been used to show that there are critical molecular mechanisms that can be activated to induce myocardial repair at specific times in development. For example, specific miRNAs are critical for regulating the response to myocardial infarction (MI) and improving the response to injury. Manipulating these miRNAs in small animal models provides beneficial effects post-MI; however it is not known if these miRNAs are regulated similarly in large mammals. Studying a large animal where the timing of heart development in relation to birth is similar to humans may provide insights to better understand the capacity to repair a developing mammalian heart and its application to the adult heart.MethodsWe used a sheep model of MI that included permanent ligation of the left anterior descending (LAD) coronary artery. Surgery was performed on fetuses (at 105 days gestation when all cardiomyocytes are mononucleated and proliferative) and adolescent sheep (at 6 months of age when all cardiomyocytes contribute to heart growth by hypertrophy). A microarray was utilized to determine the expression of known miRNAs within the damaged and undamaged tissue regions in fetal and adolescent hearts after MI.Results73 miRNAs were up-regulated and 58 miRNAs were down-regulated significantly within the fetal infarct compared to remote cardiac samples. From adolescent hearts 69 non-redundant miRNAs were up-regulated and 63 miRNAs were down-regulated significantly in the infarct area compared to remote samples. Opposite differential expression profiles of 10 miRNAs within tissue regions (Infarct area, Border zone and Remote area of the left ventricle) occurred between the fetuses and adolescent sheep. These included miR-558 and miR-1538, which when suppressed using LNA anti-miRNAs in cell culture, increased cardiomyoblast proliferation.ConclusionThere were significant differences in miRNA responses in fetal and adolescent sheep hearts following a MI, suggesting that the modulation of novel miRNA expression may have therapeutic potential, by promoting proliferation or repair in a damaged heart.
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spelling doaj.art-216866ef0c1f406893f32f76643d52632022-12-22T01:44:43ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2020-06-011110.3389/fphys.2020.00614545847Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep HeartsMitchell C. Lock0Ross L. Tellam1Jack R. T. Darby2Jia Yin Soo3Doug A. Brooks4Doug A. Brooks5Mike Seed6Joseph B. Selvanayagam7Janna L. Morrison8Early Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, AustraliaEarly Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, AustraliaEarly Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, AustraliaEarly Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, AustraliaEarly Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, AustraliaMechanisms in Cell Biology and Disease Research Group, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, AustraliaDivision of Cardiology, The Hospital for Sick Children, Toronto, ON, CanadaCardiac Imaging Research, Department of Heart Health, South Australian Health & Medical Research Institute, Flinders University, Adelaide, SA, AustraliaEarly Origins of Adult Health Research Group, University of South Australia, Adelaide, SA, AustraliaAimsAnimal models have been used to show that there are critical molecular mechanisms that can be activated to induce myocardial repair at specific times in development. For example, specific miRNAs are critical for regulating the response to myocardial infarction (MI) and improving the response to injury. Manipulating these miRNAs in small animal models provides beneficial effects post-MI; however it is not known if these miRNAs are regulated similarly in large mammals. Studying a large animal where the timing of heart development in relation to birth is similar to humans may provide insights to better understand the capacity to repair a developing mammalian heart and its application to the adult heart.MethodsWe used a sheep model of MI that included permanent ligation of the left anterior descending (LAD) coronary artery. Surgery was performed on fetuses (at 105 days gestation when all cardiomyocytes are mononucleated and proliferative) and adolescent sheep (at 6 months of age when all cardiomyocytes contribute to heart growth by hypertrophy). A microarray was utilized to determine the expression of known miRNAs within the damaged and undamaged tissue regions in fetal and adolescent hearts after MI.Results73 miRNAs were up-regulated and 58 miRNAs were down-regulated significantly within the fetal infarct compared to remote cardiac samples. From adolescent hearts 69 non-redundant miRNAs were up-regulated and 63 miRNAs were down-regulated significantly in the infarct area compared to remote samples. Opposite differential expression profiles of 10 miRNAs within tissue regions (Infarct area, Border zone and Remote area of the left ventricle) occurred between the fetuses and adolescent sheep. These included miR-558 and miR-1538, which when suppressed using LNA anti-miRNAs in cell culture, increased cardiomyoblast proliferation.ConclusionThere were significant differences in miRNA responses in fetal and adolescent sheep hearts following a MI, suggesting that the modulation of novel miRNA expression may have therapeutic potential, by promoting proliferation or repair in a damaged heart.https://www.frontiersin.org/article/10.3389/fphys.2020.00614/fullcardiacregenerationfetusmyocardial infarctionmiRNA
spellingShingle Mitchell C. Lock
Ross L. Tellam
Jack R. T. Darby
Jia Yin Soo
Doug A. Brooks
Doug A. Brooks
Mike Seed
Joseph B. Selvanayagam
Janna L. Morrison
Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts
Frontiers in Physiology
cardiac
regeneration
fetus
myocardial infarction
miRNA
title Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts
title_full Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts
title_fullStr Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts
title_full_unstemmed Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts
title_short Identification of Novel miRNAs Involved in Cardiac Repair Following Infarction in Fetal and Adolescent Sheep Hearts
title_sort identification of novel mirnas involved in cardiac repair following infarction in fetal and adolescent sheep hearts
topic cardiac
regeneration
fetus
myocardial infarction
miRNA
url https://www.frontiersin.org/article/10.3389/fphys.2020.00614/full
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