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

Abstract

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 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.

We thank Rodolphe Guinamard and Johnathan Ewbank and Jeffrey S. Friedman for helpful discussions; Marc Bajenoff, Marc Barad, Mathieu Fallet, and Nicole Brun for assistance in confocal microscopy and flow cytofluorometric analysis; and Marie Françoise Luciani for fluorescence microscopy.

This study was supported by institutional grants from INSERM and CNRS as well as charitable funds from the Association pour la Recherche contre le Cancer (ARC 5945) and Association F. Aupetit (AFA). F. Martin, C. Berruyer, and F. Malergue were recipients of a grant from the Ministère de l'Education Nationale, de la recherche et de la Technologie and of the Ligue Nationale contre le Cancer (LNCC).