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

Author:

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

Affiliation:

1. Centre d'Immunologie de Marseille-Luminy CNRS-INSERM-Université de la Méditerranée, 13288 Marseille

2. Dipartimento di Scienze Biochimiche “A. Rossi Fanelli,” Instituto di Biologia e Patologia Molecolari del CNR, Università di Roma “La Sapienza,” 00185 Rome

3. INSERM U599, 13009 Marseille, France

4. Dipartimento di Biologia di Base ed Applicata, Università di L'Aquila, Coppito L'Aquila, Italy

Abstract

ABSTRACT Vanin-1 is an epithelial ectoenzyme with pantetheinase activity and generating the amino-thiol cysteamine through the metabolism of pantothenic acid (vitamin B 5 ). Here we show that Vanin-1 −/− mice, which lack cysteamine in tissues, exhibit resistance to oxidative injury induced by whole-body γ-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.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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