title: Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression.
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 ubiquitous 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.
authors.affiliation: Animal Facility, Autonomous University of Madrid, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Miró-Murillo
authors.forename: Ainara
authors.initials: A
authors.lastname: Elorza
authors.forename: Inés
authors.initials: I
authors.lastname: Soro-Arnáiz
authors.forename: Lucas
authors.initials: L
authors.lastname: Albacete-Albacete
authors.forename: Angel
authors.initials: A
authors.lastname: Ordoñez
authors.forename: Eduardo
authors.initials: E
authors.lastname: Balsa
authors.forename: Alicia
authors.initials: A
authors.lastname: Vara-Vega
authors.forename: Silvia
authors.initials: S
authors.lastname: Vázquez
authors.forename: Esther
authors.initials: E
authors.lastname: Fuertes
authors.forename: Carmen
authors.initials: C
authors.lastname: Fernández-Criado
authors.forename: Manuel O
authors.initials: MO
authors.lastname: Landázuri
authors.forename: Julián
authors.initials: J
authors.lastname: Aragonés
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D004032:Diet; D004921:Erythropoietin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*
chemical_list: D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495678:Slc2a1 protein, mouse; D013629:Tamoxifen; D004921:Erythropoietin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C045073:Cre recombinase; D019426:Integrases; C494469:VHL protein, mouse