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Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target

BACKGROUND: Receptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart. METHODS: RTK gene expression was analyzed from h...

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Autores principales: Heliste, Juho, Jokilammi, Anne, Paatero, Ilkka, Chakroborty, Deepankar, Stark, Christoffer, Savunen, Timo, Laaksonen, Maria, Elenius, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196006/
https://www.ncbi.nlm.nih.gov/pubmed/30342492
http://dx.doi.org/10.1186/s12872-018-0933-y
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author Heliste, Juho
Jokilammi, Anne
Paatero, Ilkka
Chakroborty, Deepankar
Stark, Christoffer
Savunen, Timo
Laaksonen, Maria
Elenius, Klaus
author_facet Heliste, Juho
Jokilammi, Anne
Paatero, Ilkka
Chakroborty, Deepankar
Stark, Christoffer
Savunen, Timo
Laaksonen, Maria
Elenius, Klaus
author_sort Heliste, Juho
collection PubMed
description BACKGROUND: Receptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart. METHODS: RTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass, was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays. RESULTS: In addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation. CONCLUSIONS: Several novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12872-018-0933-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-61960062018-10-30 Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target Heliste, Juho Jokilammi, Anne Paatero, Ilkka Chakroborty, Deepankar Stark, Christoffer Savunen, Timo Laaksonen, Maria Elenius, Klaus BMC Cardiovasc Disord Research Article BACKGROUND: Receptor tyrosine kinases (RTK) are potential targets for the treatment of ischemic heart disease. The human RTK family consists of 55 members, most of which have not yet been characterized for expression or activity in the ischemic heart. METHODS: RTK gene expression was analyzed from human heart samples representing healthy tissue, acute myocardial infarction or ischemic cardiomyopathy. As an experimental model, pig heart with ischemia-reperfusion injury, caused by cardiopulmonary bypass, was used, from which phosphorylation status of RTKs was assessed with a phospho-RTK array. Expression and function of one RTK, ROR1, was further validated in pig tissue samples, and in HL-1 cardiomyocytes and H9c2 cardiomyoblasts, exposed to hypoxia and reoxygenation. ROR1 protein level was analyzed by Western blotting. Cell viability after ROR1 siRNA knockdown or activation with Wnt-5a ligand was assessed by MTT assays. RESULTS: In addition to previously characterized RTKs, a group of novel active and regulated RTKs was detected in the ischemic heart. ROR1 was the most significantly upregulated RTK in human ischemic cardiomyopathy. However, ROR1 phosphorylation was suppressed in the pig model of ischemia-reperfusion and ROR1 phosphorylation and expression were down-regulated in HL-1 cardiomyocytes subjected to short-term hypoxia in vitro. ROR1 expression in the pig heart was confirmed on protein and mRNA level. Functionally, ROR1 activity was associated with reduced viability of HL-1 cardiomyocytes in both normoxia and during hypoxia-reoxygenation. CONCLUSIONS: Several novel RTKs were found to be regulated in expression or activity in ischemic heart. ROR1 was one of the most significantly regulated RTKs. The in vitro findings suggest a role for ROR1 as a potential target for the treatment of ischemic heart injury. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12872-018-0933-y) contains supplementary material, which is available to authorized users. BioMed Central 2018-10-20 /pmc/articles/PMC6196006/ /pubmed/30342492 http://dx.doi.org/10.1186/s12872-018-0933-y Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Heliste, Juho
Jokilammi, Anne
Paatero, Ilkka
Chakroborty, Deepankar
Stark, Christoffer
Savunen, Timo
Laaksonen, Maria
Elenius, Klaus
Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target
title Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target
title_full Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target
title_fullStr Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target
title_full_unstemmed Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target
title_short Receptor tyrosine kinase profiling of ischemic heart identifies ROR1 as a potential therapeutic target
title_sort receptor tyrosine kinase profiling of ischemic heart identifies ror1 as a potential therapeutic target
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196006/
https://www.ncbi.nlm.nih.gov/pubmed/30342492
http://dx.doi.org/10.1186/s12872-018-0933-y
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