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

2004; Taylor & Francis; Volume: 24; Issue: 16 Linguagem: Inglês

10.1128/mcb.24.16.7214-7224.2004

1098-5549

Carole Berruyer-Pouyet, Florent Martin, Rémy Castellano, Alberto Macone, Fabrice Malergue, Sarah Garrido‐Urbani, Virginie Millet, Jean Imbert, Silvestro Duprè, Giuseppina Pitari, Philippe Naquet, Franck Galland,

Porphyrin Metabolism and Disorders

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 gamma-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.