Induction of endothelin-converting enzyme-1 in gastric mucosal injury by idomethacin.
Endothelin-1 (ET-1) is a 21-amino acid vasoactive peptide produced from a 39-amino acid biologically inactive peptide, big ET-1, by the action of endothelin-converting enzyme-1 (ECE-1). We investigated gastric mucosal expression of ECE-1 during a 16 h course of inflammatory responses associated with gastric mucosal injury caused by indomethacin. The extent of gastric mucosal damage reached a maximum 4 h following the drug, and was accompanied by a 3.9-fold enhancement in the expression of ECE-1 activity and a significant elevation in ET-1 (4.5-fold), TNF-alpha (11.3-fold), and apoptosis (29.9-fold). A 37.2% decrease in the severity of lesion 16 h following the drug was associated with a 44.5% reduction in the mucosal expression of ECE-1 activity and a decline in TNF-alpha (64%), ET-1 (65.2%), and apoptosis (72.3%). The results demonstrate that gastric mucosal injury by indomethacin is associated with up-regulation of ECE-1 expression, which leads to the enhancement of ET-1 production, induction of TNF-alpha, and triggering apoptotic events that disrupt gastric mucosal homeostasis.
Slomiany
B L
BL
Research Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, 07103-2400, USA. slomiabr@umdnj.edu
Slomiany
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis*; D000072396:Endothelin-Converting Enzymes; D004790:Enzyme Induction; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D007213:Indomethacin / Q000009:adverse effects*; D008666:Metalloendopeptidases; D051381:Rats; D017207:Rats, Sprague-Dawley
D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D007213:Indomethacin