Acute Vhl gene inactivation induces cardiac HIF-Dependent erythropoietin gene expression
Date
2011-07-21Citation
PLoS ONE 6.7 (2011): e22589ISSN
1932-6203 (online)Funded by
This work was supported by grants from Ministerio de Educación y Ciencia (BFU2008-03407/BMC), RECAVA (RD06/0014/0031), CICYT (SAF2007-60592) and CAM (SAL0311/2006). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Project
Comunidad de Madrid. S2006/SAL-0311Subjects
Erythropoietin; Procollagen Proline 2 Oxoglutarate 4 Dioxygenase; Polycythemia; Animals; Gene Expression Regulation; Gene Silencing; MedicinaRights
© 2011 Miró-Murillo et al.Abstract
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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Google Scholar:Miró-Murillo, Marta
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Elorza, Ainara
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Soro Arnáiz, Inés
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Albacete Albacete, Lucas
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Ordóñez, Ángel
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Balsa Martínez, Eduardo
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Vara-Vega, Alicia
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Vázquez, Silvia
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Fuertes, Esther
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Fernández-Criado, Carmen
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Landázuri, Manuel O.
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Aragonés López, Julián
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