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iNOS-derived nitric oxide mediates the increase in TFF2 expression associated with gastric damage: role of HIF-1

Dolores Ortiz-Masiá^*,,1, Carlos Hernández^,1, Elsa Quintana, Miriam Velázquez^*,, Sonia Cebrián, Annia Riaño, Sara Calatayud^*,, Juan V. Esplugues^*, and Maria D. Barrachina^*,,2

^* Departamento de Farmacología and

CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

² Correspondence: Department of Pharmacology, Faculty of Medicine, University of Valencia, Avda. Blasco Ibáñez, 15-17, 46010 Valencia Spain. E-mail: dolores.barrachina{at}uv.es

Trefoil (TFF) peptides are involved in gastrointestinal mucosal restitution. An hypoxia inducible factor 1 (HIF-1)-dependent induction of TFF genes has been reported in gastric epithelial cells. Nitric oxide (NO) is associated with mucosal damage and modulates HIF-1 activity. The aim of the present study was to analyze the role of iNOS-derived NO in HIF-1 stabilization and TFF gene expression in damaged gastric mucosa. Aspirin caused gastric injury that peaked 6 h after dosing and returned to normality at 24 h. iNOS mRNA expression occurs in the corpus in parallel with damage. Blockade of iNOS activity did not modify gastric lesions induced by aspirin but delayed mucosal healing. Aspirin induced HIF-1 stabilization and TFF2 mRNA up-regulation in the mucosa, but these effects were diminished when iNOS activity was inhibited. Results obtained using a coculture setup showed that iNOS-derived NO from activated macrophages induced HIF-1 stabilization, TFF gene expression, and accelerated wound healing in cultured epithelial cells. Finally, transient silencing of endogenous HIF-1 in epithelial cells significantly undermined activated macrophage-induced TFF gene expression. Evidence suggests that the iNOS-derived NO associated with NSAID-induced gastric injury is implicated in mucosal restitution via the HIF-1-mediated induction of TFF genes.—Ortiz-Masiá, D., Hernández, C., Quintana, E., Velázquez, M., Cebrián, S., Riaño, A., Calatayud, S., Esplugues, J. V., Barrachina, M. D. iNOS-derived nitric oxide mediates the increase in TFF2 expression associated with gastric damage: role of HIF-1.

Key Words: NSAID gastropathy • macrophage activation • mucosal restitution • inducible nitric oxide synthase