Cyclooxygenase-2 mediates hydrogen peroxide-induced wound repair in human endothelial cells.
Cyclooxygenase-2 (Cox-2) metabolites produced by endothelial cells, particularly prostacyclin and prostaglandin E(2), profoundly affect vascular tone, regional blood flow, and angiogenesis. We have previously shown that reactive oxygen species induce Cox-2 expression in human endothelial cells (HUVEC), either on their own or as components of the signaling pathway triggered by TNFalpha, the prototypical inflammatory cytokine. Here we investigated the role of Cox-2 induced by hydrogen peroxide (H(2)O(2)), either exogenous or endogenously generated by TNFalpha, in the repair of a mechanically wounded HUVEC monolayer and probed the sources of H(2)O(2) that are involved in TNFalpha signaling and the pathways through which H(2)O(2) modulates Cox-2 expression. Results indicate that H(2)O(2)-induced Cox-2 activity participates in the repair of wounded monolayers. Both NADPH oxidase and the mitochondrial electron transport chain are involved in H(2)O(2) generation. Signaling triggered by H(2)O(2) for Cox-2 induction acts by increasing the protein tyrosine kinase phosphorylation that follows inhibition of protein phosphatase activity. The activation of p38 MAPK and its interaction in the inhibition of serine/threonine phosphatase activity are both critical steps in this event. We conclude that Cox-2 induced by H(2)O(2) plays an important role in promoting endothelial wound repair after injury, so that the cardioprotective effect of Cox-2 is due at least in part to its power of healing damaged endothelium.
Eligini
Sonia
S
E. Grossi Paoletti Center, Department of Pharmacological Sciences, University of Milan, Italy.
Arenaz
Izaskun
I
Barbieri
Silvia S
SS
Faleri
Maurizio L
ML
Crisci
Mauro
M
Tremoli
Elena
E
Colli
Susanna
S
D002316:Cardiotonic Agents / Q000378:metabolism*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004579:Electron Transport; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002316:Cardiotonic Agents; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases