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Vanin-1^–/– Mice Exhibit a Glutathione-Mediated Tissue Resistance to Oxidative Stress

C. Berruyer,^1, F. M. Martin,^1,, R. Castellano,¹ A. Macone,² F. Malergue,¹ S. Garrido-Urbani,¹ V. Millet,¹ J. Imbert,³ S. Duprè,² G. Pitari,⁴ P. Naquet,¹ and F. Galland^1*

Centre d'Immunologie de Marseille-Luminy CNRS-INSERM-Université de la Méditerranée, 13288 Marseille,¹ INSERM U599, 13009 Marseille, France,³ Dipartimento di Scienze Biochimiche "A. Rossi Fanelli," Instituto di Biologia e Patologia Molecolari del CNR, Università di Roma "La Sapienza," 00185 Rome,² Dipartimento di Biologia di Base ed Applicata, Università di L'Aquila, Coppito L'Aquila, Italy⁴

Received 6 January 2004/ Returned for modification 9 February 2004/ Accepted 6 May 2004

Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B₅). Here we show that Vanin-1^–/– mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body -irradiation or paraquat. This protection is correlated with reduced apoptosis and inflammation and is reversed by treating mutant animals with cystamine. The better tolerance of the Vanin-1^–/– mice is associated with an enhanced gamma-glutamylcysteine synthetase activity in liver, probably due to the absence of cysteamine and leading to elevated stores of glutathione (GSH), the most potent cellular antioxidant. Consequently, Vanin-1^–/– mice maintain a more reducing environment in tissue after exposure to irradiation. In normal mice, we found a stress-induced biphasic expression of Vanin-1 regulated via antioxidant response elements in its promoter region. This process should finely tune the redox environment and thus change an early inflammatory process into a late tissue repair process. We propose Vanin-1 as a key molecule to regulate the GSH-dependent response to oxidative injury in tissue at the epithelial level. Therefore, Vanin/pantetheinase inhibitors could be useful for treatment of damage due to irradiation and pro-oxidant inducers.

C.B. and F.M.M. contributed equally to this work.

Present address: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037.

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