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Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression

Von Hippel Lindau (Vhl) gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs), have been explored mainly in a tissue-specific manner. This mid-gestation lethality can be also circumv...

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Autores principales: Miró-Murillo, Marta, Elorza, Ainara, Soro-Arnáiz, Inés, Albacete-Albacete, Lucas, Ordoñez, Angel, Balsa, Eduardo, Vara-Vega, Alicia, Vázquez, Silvia, Fuertes, Esther, Fernández-Criado, Carmen, Landázuri, Manuel O., Aragonés, Julián
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141062/
https://www.ncbi.nlm.nih.gov/pubmed/21811636
http://dx.doi.org/10.1371/journal.pone.0022589
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author Miró-Murillo, Marta
Elorza, Ainara
Soro-Arnáiz, Inés
Albacete-Albacete, Lucas
Ordoñez, Angel
Balsa, Eduardo
Vara-Vega, Alicia
Vázquez, Silvia
Fuertes, Esther
Fernández-Criado, Carmen
Landázuri, Manuel O.
Aragonés, Julián
author_facet Miró-Murillo, Marta
Elorza, Ainara
Soro-Arnáiz, Inés
Albacete-Albacete, Lucas
Ordoñez, Angel
Balsa, Eduardo
Vara-Vega, Alicia
Vázquez, Silvia
Fuertes, Esther
Fernández-Criado, Carmen
Landázuri, Manuel O.
Aragonés, Julián
author_sort Miró-Murillo, Marta
collection PubMed
description Von Hippel Lindau (Vhl) gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs), have been explored mainly in a tissue-specific manner. This mid-gestation lethality can be also circumvented by using a floxed Vhl allele in combination with an ubiquous tamoxifen-inducible recombinase Cre-ER(T2). Here, we characterize a widespread reduction in Vhl gene expression in Vhl(floxed)-UBC-Cre-ER(T2) adult mice after dietary tamoxifen administration, a convenient route of administration that has yet to be fully characterized for global gene inactivation. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin (Epo) gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We show that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL-1 cardiac cells both induce Epo gene expression when exposed to low O(2) tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER(T2) mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice.
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spelling pubmed-31410622011-08-02 Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression Miró-Murillo, Marta Elorza, Ainara Soro-Arnáiz, Inés Albacete-Albacete, Lucas Ordoñez, Angel Balsa, Eduardo Vara-Vega, Alicia Vázquez, Silvia Fuertes, Esther Fernández-Criado, Carmen Landázuri, Manuel O. Aragonés, Julián PLoS One Research Article Von Hippel Lindau (Vhl) gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs), have been explored mainly in a tissue-specific manner. This mid-gestation lethality can be also circumvented by using a floxed Vhl allele in combination with an ubiquous tamoxifen-inducible recombinase Cre-ER(T2). Here, we characterize a widespread reduction in Vhl gene expression in Vhl(floxed)-UBC-Cre-ER(T2) adult mice after dietary tamoxifen administration, a convenient route of administration that has yet to be fully characterized for global gene inactivation. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin (Epo) gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We show that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL-1 cardiac cells both induce Epo gene expression when exposed to low O(2) tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER(T2) mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice. Public Library of Science 2011-07-21 /pmc/articles/PMC3141062/ /pubmed/21811636 http://dx.doi.org/10.1371/journal.pone.0022589 Text en Miró-Murillo et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Miró-Murillo, Marta
Elorza, Ainara
Soro-Arnáiz, Inés
Albacete-Albacete, Lucas
Ordoñez, Angel
Balsa, Eduardo
Vara-Vega, Alicia
Vázquez, Silvia
Fuertes, Esther
Fernández-Criado, Carmen
Landázuri, Manuel O.
Aragonés, Julián
Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression
title Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression
title_full Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression
title_fullStr Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression
title_full_unstemmed Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression
title_short Acute Vhl Gene Inactivation Induces Cardiac HIF-Dependent Erythropoietin Gene Expression
title_sort acute vhl gene inactivation induces cardiac hif-dependent erythropoietin gene expression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141062/
https://www.ncbi.nlm.nih.gov/pubmed/21811636
http://dx.doi.org/10.1371/journal.pone.0022589
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