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Originally published In Press as doi:10.1074/jbc.M702639200 on August 2, 2007

J. Biol. Chem., Vol. 282, Issue 41, 30207-30215, October 12, 2007
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Development of Cytosolic Hypoxia and Hypoxia-inducible Factor Stabilization Are Facilitated by Aquaporin-1 Expression*Formula

Miriam Echevarría1, Ana M. Muñoz-Cabello12, Rocío Sánchez-Silva, Juan J. Toledo-Aral, and José López-Barneo3

From the Laboratorio de Investigaciones Biomédicas, Departamento de Fisiología Médica y Biofísica, Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, 41013 Spain

O2 is essential for aerobic life, and the classic view is that it diffuses freely across the plasma membrane. However, measurements of O2 permeability of lipid bilayers have indicated that it is much lower than previously thought, and therefore, the existence of membrane O2 channels has been suggested. We hypothesized that, besides its role as a water channel, aquaporin-1 (AQP-1) could also work as an O2 transporter, because this transmembrane protein appears to be CO2-permeable and is highly expressed in cells with rapid O2 turnover (erythrocytes and microvessel endothelium). Here we show that in mammalian cells overexpressing AQP-1 and exposed to hypoxia, the loss of cytosolic O2, as well as stabilization of the O2-dependent hypoxia-inducible transcription factor and expression of its target genes, is accelerated. In normoxic endothelial cells, knocking down AQP-1 produces induction of hypoxia-inducible genes. Moreover, lung AQP-1 is markedly up-regulated in animals exposed to hypoxia. These data suggest that AQP-1 has O2 permeability and thus could facilitate O2 diffusion across the cell membrane.


Received for publication, March 27, 2007 , and in revised form, July 31, 2007.

* This work was funded in part by Ayuda a la Investigación 2000 of the Juan March Foundation and by grants from the Instituto de Salud Carlos III PI 030296 and Consejería de Salud, Junta de Andalucía, 22/02. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Formula The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

1 Both authors contributed equally to this work.

2 Supported by a predoctoral fellowship from the Spanish Ministries of Health and of Education.

3 To whom correspondence should be addressed: Laboratorio de Investigaciones Biomédicas, Edificio de Laboratorios, 2 planta, Hospital Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain. Tel.: 34-955-012648; Fax: 34-954-617301; E-mail: lbarneo{at}us.es.


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