Activation of Apoptotic Caspase-3 and Nitric Oxide Synthase-2 in Gastric Mucosal Injury Induced by Indomethacin

Abstract

Background: Apoptosis is the process of programmed cell death characterized by a series of distinct biochemical and morphologic changes involving activation of the caspase protease, cascade, which remains under the regulatory control of nitric oxide. In this study we investigated the activity of a key apoptotic protease, caspase-3, and the expression of inducible nitric oxide synthase (NOS-2) associated with gastric epithelial cell apoptosis during indomethacin-induced gastric mucosal injury. Methods: The experiments were conducted with groups of rats subjected to intragastric administration of 60 mg/kg indomethacin or the vehicle. After 2 h the animals were killed and their gastric mucosal tissue used for macroscopic assessment, assays of epithelial cell apoptosis, and the measurement of caspase-3 and NOS-2 activities. Results: Indomethacin caused extensive multiple hemorrhagic lesions accompanied by marked enhancement in epithelial cell apoptosis, a 3.9-fold increase in mucosal expression of caspase-3 activity, and an 11.9-fold induction in NOS-2. Moreover, the mucosal expression of NOS-2 showed a positive correlation with the extent of changes induced in caspase-3 activity. Conclusions: The results implicate caspase-3 in the process of indomethacin-induced gastric epithelial cell apoptosis and point towards participation of NOS-2 in the amplification of the cell death signaling cascade, hence contributing to the extent of mucosal injury.