title: Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice.
abstract: Mitochondrial superoxide dismutase (SOD2) prevents accumulation of the superoxide that arises as a consequence of oxidative phosphorylation. However, SOD2 is a target of oxidative/nitrosative inactivation, and reduced SOD2 activity has been demonstrated to contribute to portal hypertensive gastropathy. We investigated the consequences of gastric parietal cell-specific SOD2 deficiency on mitochondrial function and gastric injury susceptibility. Mice expressing Cre recombinase under control of the parietal cell Atpase4b gene promoter were crossed with mice harboring loxP sequences flanking the sod2 gene (SOD2 floxed mice). Cre-positive mice and Cre-negative littermates (controls) were used in studies of SOD2 expression, parietal cell function (ATP synthesis, acid secretion, and mitochondrial enzymatic activity), increased oxidative/nitrosative stress, and gastric susceptibility to acute injury. Parietal cell SOD2 deficiency was accompanied by a 20% (P < 0.05) reduction in total gastric SOD activity and a 93% (P < 0.001) reduction in gastric SOD2 activity. In SOD2-deficient mice, mitochondrial aconitase and ATP synthase activities were impaired by 36% (P < 0.0001) and 44% (P < 0.005), respectively. Gastric tissue ATP content was reduced by 34% (P < 0.002). Basal acid secretion and peak secretagogue (histamine)-induced acid secretion were reduced by 43% (P < 0.0001) and 40% (P < 0.0005), respectively. There was a fourfold (P < 0.02) increase in gastric mucosal apoptosis and 41% (P < 0.001) greater alcohol-induced gastric damage in the parietal cell SOD2-deficient mice. Our findings indicate that loss of parietal cell SOD2 leads to mitochondrial dysfunction, resulting in perturbed energy metabolism, impaired parietal cell function, and increased gastric mucosal oxidative stress. These alterations render the gastric mucosa significantly more susceptible to acute injury.
authors: Research Healthcare Group, Veterans Affairs Long Beach Healthcare System, Long Beach, CA 90822, USA.
authors: Michael K
authors: MK
authors: Jones
authors: Ercheng
authors: E
authors: Zhu
authors: Edna V
authors: EV
authors: Sarino
authors: Oscar R
authors: OR
authors: Padilla
authors: Takamune
authors: T
authors: Takahashi
authors: Takahiko
authors: T
authors: Shimizu
authors: Takuji
authors: T
authors: Shirasawa
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000293:injuries / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology*; D010295:Parietal Cells, Gastric / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000154:Aconitate Hydratase; D025261:Mitochondrial Proton-Translocating ATPases; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C501006:mt-Atp6 protein, mouse