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Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation

BACKGROUND: Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critic...

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Autores principales: Sharma, Vipul, Goessling, Lisa S., Brar, Anoop K., Joshi, Chetanchandra S., Mysorekar, Indira U., Eghtesady, Pirooz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955305/
https://www.ncbi.nlm.nih.gov/pubmed/33440998
http://dx.doi.org/10.1161/JAHA.120.017995
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author Sharma, Vipul
Goessling, Lisa S.
Brar, Anoop K.
Joshi, Chetanchandra S.
Mysorekar, Indira U.
Eghtesady, Pirooz
author_facet Sharma, Vipul
Goessling, Lisa S.
Brar, Anoop K.
Joshi, Chetanchandra S.
Mysorekar, Indira U.
Eghtesady, Pirooz
author_sort Sharma, Vipul
collection PubMed
description BACKGROUND: Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. METHODS AND RESULTS: We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose‐response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double‐outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3‐exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor‐β1, and extracellular matrix proteins were the most highly enriched in CVB3‐infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. CONCLUSIONS: We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes.
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spelling pubmed-79553052021-03-17 Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation Sharma, Vipul Goessling, Lisa S. Brar, Anoop K. Joshi, Chetanchandra S. Mysorekar, Indira U. Eghtesady, Pirooz J Am Heart Assoc Original Research BACKGROUND: Coxsackievirus B (CVB) is the most common cause of viral myocarditis. It targets cardiomyocytes through coxsackie and adenovirus receptor, which is highly expressed in the fetal heart. We hypothesized CVB3 can precipitate congenital heart defects when fetal infection occurs during critical window of gestation. METHODS AND RESULTS: We infected C57Bl/6 pregnant mice with CVB3 during time points in early gestation (embryonic day [E] 5, E7, E9, and E11). We used different viral titers to examine possible dose‐response relationship and assessed viral loads in various fetal organs. Provided viral exposure occurred between E7 and E9, we observed characteristic features of ventricular septal defect (33.6%), abnormal myocardial architecture resembling noncompaction (23.5%), and double‐outlet right ventricle (4.4%) among 209 viable fetuses examined. We observed a direct relationship between viral titers and severity of congenital heart defects, with apparent predominance among female fetuses. Infected dams remained healthy; we did not observe any maternal heart or placental injury suggestive of direct viral effects on developing heart as likely cause of congenital heart defects. We examined signaling pathways in CVB3‐exposed hearts using RNA sequencing, Kyoto Encyclopedia of Genes and Genomes enrichment analysis, and immunohistochemistry. Signaling proteins of the Hippo, tight junction, transforming growth factor‐β1, and extracellular matrix proteins were the most highly enriched in CVB3‐infected fetuses with ventricular septal defects. Moreover, cardiomyocyte proliferation was 50% lower in fetuses with ventricular septal defects compared with uninfected controls. CONCLUSIONS: We conclude prenatal CVB3 infection induces congenital heart defects. Alterations in myocardial proliferate capacity and consequent changes in cardiac architecture and trabeculation appear to account for most of observed phenotypes. John Wiley and Sons Inc. 2021-01-14 /pmc/articles/PMC7955305/ /pubmed/33440998 http://dx.doi.org/10.1161/JAHA.120.017995 Text en © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Sharma, Vipul
Goessling, Lisa S.
Brar, Anoop K.
Joshi, Chetanchandra S.
Mysorekar, Indira U.
Eghtesady, Pirooz
Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation
title Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation
title_full Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation
title_fullStr Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation
title_full_unstemmed Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation
title_short Coxsackievirus B3 Infection Early in Pregnancy Induces Congenital Heart Defects Through Suppression of Fetal Cardiomyocyte Proliferation
title_sort coxsackievirus b3 infection early in pregnancy induces congenital heart defects through suppression of fetal cardiomyocyte proliferation
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955305/
https://www.ncbi.nlm.nih.gov/pubmed/33440998
http://dx.doi.org/10.1161/JAHA.120.017995
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