Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.

<h4>Background</h4>The epidermal growth factor (EGF) receptors HER2 and HER4 and the ligands HB-EGF and NRG1 are crucial for heart development. The purpose of our study was to investigate the role of the complete EGF system in relation to hypoxia of the heart.<h4>Methodology/princi...

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Autores principales:	Mathias Munk, Ashfaque Ahmed Memon, Jens Peter Goetze, Lars Bo Nielsen, Ebba Nexo, Boe Sandahl Sorensen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fd83521d64084aa0b6923d0e45dbbaae
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spelling	oai:doaj.org-article:fd83521d64084aa0b6923d0e45dbbaae2021-11-18T07:13:22ZHypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.1932-620310.1371/journal.pone.0040243https://doaj.org/article/fd83521d64084aa0b6923d0e45dbbaae2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22792252/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>The epidermal growth factor (EGF) receptors HER2 and HER4 and the ligands HB-EGF and NRG1 are crucial for heart development. The purpose of our study was to investigate the role of the complete EGF system in relation to hypoxia of the heart.<h4>Methodology/principal findings</h4>We examined the mRNA expression by real time PCR of the 4 receptors and 12 ligands from the EGF-system in paired normoxic and hypoxic biopsies isolated from human hearts during coronary artery bypass operation. Compared to normoxic biopsies, hypoxic samples showed down-regulation of HER2 (P = 0.0005) and NRG1 (both α (P = 0.02) and β (P = 0.03) isoforms). In contrast, HB-EGF (P = 0.0008), NRG2β (P = 0.01) and EGFR (P = 0.02) were up-regulated. As HER2 is essential for heart development and we find its expression reduced under hypoxia we investigated the effect of HER2 inhibition in hypoxic HL-1 cardiomyocytes by treatment with trastuzumab (20 nM). This resulted in inhibition of cardiomyocyte proliferation, but interestingly only in hypoxic cells. Co-treatment of HL-1 cells with HB-EGF (10 nM) but not with NRG-1 (5 ng/ml) rescued the cardiomyocytes from HER2 inhibition. HL-1 cardiomyocytes exposed to hypoxia revealed nuclear translocation of activated MAPK and the activity of this downstream signaling molecule was decreased by HER2 inhibition (20 nM trastuzumab), and re-established by HB-EGF (10 nM).<h4>Conclusions/significance</h4>Hypoxia in the human heart alters the expression of the EGF system. Mimicking the HER2 down-regulation seen in the human heart in cultured cardiomyocytes inhibited their proliferation under hypoxic conditions. Interestingly, HB-EGF is induced in the hypoxic human hearts, and rescues hypoxic cardiomyocytes from the effect of HER2 inhibition in the in vitro model. The results have implications for future treatment strategies of patients with ischemic heart disease.Mathias MunkAshfaque Ahmed MemonJens Peter GoetzeLars Bo NielsenEbba NexoBoe Sandahl SorensenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 7, p e40243 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mathias Munk Ashfaque Ahmed Memon Jens Peter Goetze Lars Bo Nielsen Ebba Nexo Boe Sandahl Sorensen Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.
description	<h4>Background</h4>The epidermal growth factor (EGF) receptors HER2 and HER4 and the ligands HB-EGF and NRG1 are crucial for heart development. The purpose of our study was to investigate the role of the complete EGF system in relation to hypoxia of the heart.<h4>Methodology/principal findings</h4>We examined the mRNA expression by real time PCR of the 4 receptors and 12 ligands from the EGF-system in paired normoxic and hypoxic biopsies isolated from human hearts during coronary artery bypass operation. Compared to normoxic biopsies, hypoxic samples showed down-regulation of HER2 (P = 0.0005) and NRG1 (both α (P = 0.02) and β (P = 0.03) isoforms). In contrast, HB-EGF (P = 0.0008), NRG2β (P = 0.01) and EGFR (P = 0.02) were up-regulated. As HER2 is essential for heart development and we find its expression reduced under hypoxia we investigated the effect of HER2 inhibition in hypoxic HL-1 cardiomyocytes by treatment with trastuzumab (20 nM). This resulted in inhibition of cardiomyocyte proliferation, but interestingly only in hypoxic cells. Co-treatment of HL-1 cells with HB-EGF (10 nM) but not with NRG-1 (5 ng/ml) rescued the cardiomyocytes from HER2 inhibition. HL-1 cardiomyocytes exposed to hypoxia revealed nuclear translocation of activated MAPK and the activity of this downstream signaling molecule was decreased by HER2 inhibition (20 nM trastuzumab), and re-established by HB-EGF (10 nM).<h4>Conclusions/significance</h4>Hypoxia in the human heart alters the expression of the EGF system. Mimicking the HER2 down-regulation seen in the human heart in cultured cardiomyocytes inhibited their proliferation under hypoxic conditions. Interestingly, HB-EGF is induced in the hypoxic human hearts, and rescues hypoxic cardiomyocytes from the effect of HER2 inhibition in the in vitro model. The results have implications for future treatment strategies of patients with ischemic heart disease.
format	article
author	Mathias Munk Ashfaque Ahmed Memon Jens Peter Goetze Lars Bo Nielsen Ebba Nexo Boe Sandahl Sorensen
author_facet	Mathias Munk Ashfaque Ahmed Memon Jens Peter Goetze Lars Bo Nielsen Ebba Nexo Boe Sandahl Sorensen
author_sort	Mathias Munk
title	Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.
title_short	Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.
title_full	Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.
title_fullStr	Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.
title_full_unstemmed	Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.
title_sort	hypoxia changes the expression of the epidermal growth factor (egf) system in human hearts and cultured cardiomyocytes.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/fd83521d64084aa0b6923d0e45dbbaae
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Hypoxia changes the expression of the epidermal growth factor (EGF) system in human hearts and cultured cardiomyocytes.

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