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Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling

AIMS: Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal‐regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen‐activated protein kinase (MAPK) pathways, modulate cardiac...

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Autores principales: Jochmann, Svenja, Elkenani, Manar, Mohamed, Belal A., Buchholz, Eric, Lbik, Dawid, Binder, Lutz, Lorenz, Kristina, Shah, Ajay M., Hasenfuß, Gerd, Toischer, Karl, Schnelle, Moritz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816056/
https://www.ncbi.nlm.nih.gov/pubmed/31322843
http://dx.doi.org/10.1002/ehf2.12497
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author Jochmann, Svenja
Elkenani, Manar
Mohamed, Belal A.
Buchholz, Eric
Lbik, Dawid
Binder, Lutz
Lorenz, Kristina
Shah, Ajay M.
Hasenfuß, Gerd
Toischer, Karl
Schnelle, Moritz
author_facet Jochmann, Svenja
Elkenani, Manar
Mohamed, Belal A.
Buchholz, Eric
Lbik, Dawid
Binder, Lutz
Lorenz, Kristina
Shah, Ajay M.
Hasenfuß, Gerd
Toischer, Karl
Schnelle, Moritz
author_sort Jochmann, Svenja
collection PubMed
description AIMS: Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal‐regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen‐activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO‐induced cardiac remodelling as this was unknown. METHODS AND RESULTS: Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr‐Glu‐Tyr) motif (−28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte‐specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6‐fold, P < 0.05) and protein level (3.1‐fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice. CONCLUSIONS: VO‐induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte‐specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.
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spelling pubmed-68160562019-10-31 Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling Jochmann, Svenja Elkenani, Manar Mohamed, Belal A. Buchholz, Eric Lbik, Dawid Binder, Lutz Lorenz, Kristina Shah, Ajay M. Hasenfuß, Gerd Toischer, Karl Schnelle, Moritz ESC Heart Fail Original Research Articles AIMS: Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal‐regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen‐activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO‐induced cardiac remodelling as this was unknown. METHODS AND RESULTS: Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr‐Glu‐Tyr) motif (−28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte‐specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6‐fold, P < 0.05) and protein level (3.1‐fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice. CONCLUSIONS: VO‐induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte‐specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO. John Wiley and Sons Inc. 2019-07-19 /pmc/articles/PMC6816056/ /pubmed/31322843 http://dx.doi.org/10.1002/ehf2.12497 Text en © 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology. 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 Articles
Jochmann, Svenja
Elkenani, Manar
Mohamed, Belal A.
Buchholz, Eric
Lbik, Dawid
Binder, Lutz
Lorenz, Kristina
Shah, Ajay M.
Hasenfuß, Gerd
Toischer, Karl
Schnelle, Moritz
Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling
title Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling
title_full Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling
title_fullStr Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling
title_full_unstemmed Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling
title_short Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling
title_sort assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling
topic Original Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816056/
https://www.ncbi.nlm.nih.gov/pubmed/31322843
http://dx.doi.org/10.1002/ehf2.12497
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