Vanin-1-/- mice exhibit a glutathione-mediated tissue resistance to oxidative stress.
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.
Berruyer
C
C
Centre d'Immunologie de Marseille-Luminy CNRS-INSERM-Université de la Méditerranée, 13288 Marseille, France
Martin
F M
FM
Castellano
R
R
Macone
A
A
Malergue
F
F
Garrido-Urbani
S
S
Millet
V
V
Imbert
J
J
Duprè
S
S
Pitari
G
G
Naquet
P
P
Galland
F
F
D000581:Amidohydrolases; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003538:Cystamine / Q000008:administration & dosage / Q000378:metabolism; D003543:Cysteamine / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D058851:GPI-Linked Proteins; D005720:Gamma Rays; D015971:Gene Expression Regulation, Enzymologic; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006540:Herbicides / Q000008:administration & dosage; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018384:Oxidative Stress; D010269:Paraquat / Q000008:administration & dosage; D011401:Promoter Regions, Genetic; D011837:Radiation-Protective Agents / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology / Q000528:radiation effects
D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D006540:Herbicides; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; D003543:Cysteamine; D000581:Amidohydrolases; C022314:pantetheinase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D010269:Paraquat; D003538:Cystamine