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

FASEB J. 2010 Jan;24(1):136-45. doi: 10.1096/fj.09-137489. Epub 2009 Sep 9.


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-1alpha 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-1alpha 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-1alpha stabilization, TFF gene expression, and accelerated wound healing in cultured epithelial cells. Finally, transient silencing of endogenous HIF-1alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidines / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / toxicity
  • Aspirin / toxicity
  • Base Sequence
  • Benzylamines / pharmacology
  • Cell Line
  • Coculture Techniques
  • DNA Primers / genetics
  • Enzyme Inhibitors / pharmacology
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / injuries*
  • Gastric Mucosa / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Macrophage Activation
  • Male
  • Mice
  • MicroRNAs / genetics
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / metabolism*
  • Peptides / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Trefoil Factor-2
  • Up-Regulation / drug effects
  • Wound Healing / physiology


  • Amidines
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzylamines
  • DNA Primers
  • Enzyme Inhibitors
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MicroRNAs
  • N-(3-(aminomethyl)benzyl)acetamidine
  • Peptides
  • RNA, Messenger
  • TFF2 protein, human
  • Tff2 protein, rat
  • Trefoil Factor-2
  • Nitric Oxide
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Aspirin