Abstract
We previously demonstrated that enteral arginine increased c-Jun/activator protein-1 (AP-1) DNA-binding activity and iNOS expression in a rodent model of mesenteric ischemia/reperfusion (I/R). The objective of this study was to specifically investigate the role of AP-1 in arginine’s deleterious effect on the postischemic gut. We hypothesized that AP-1 inhibition would mitigate the effects of arginine. Using a rodent model of mesenteric I/R we demonstrated that gut neutrophil infiltration, activity of c-Jun/AP-1, as well as iNOS expression were increased by I/R and further increased by arginine while lessened by inhibition of c-Jun using the pharmacologic c-Jun N-terminal kinase inhibitor, SP600125. Similar results were demonstrated using a cell culture model of oxidant stress in IEC-6 cells. Importantly, effects of SP600125 were comparable to those of c-Jun silencing. Lastly, the specific iNOS inhibitor, 1400W, had no effect on either AP-1 or c-Jun. In conclusion, SP600125 attenuated the activity of c-Jun/AP-1, iNOS expression, and neutrophil infiltration induced by arginine following mesenteric I/R. Our data suggest that AP-1 inhibition mitigates the injurious inflammatory effects of arginine in the postischemic gut. Further investigation into the pathologic role of enteral argninine in the postischemic gut is warranted.
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Abbreviations
- AP-1:
-
Activator protein 1
- DMSO:
-
Dimethyl sulfoxide
- EMSA:
-
Electrophoretic mobility shift assay
- H2O2 :
-
Hydrogen peroxide
- iNOS:
-
Inducible nitric oxide synthase
- I/R:
-
Ischemia/reperfusion
- JNK:
-
c-Jun N-terminal kinase
- MPO:
-
Myeloperoxidase
- PPARγ:
-
Peroxisome proliferator activated receptor gamma
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This study was supported by grants from the National Institutes of Health (RO1GM077282).
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Ban, K., Santora, R. & Kozar, R.A. Enteral arginine modulates inhibition of AP-1/c-Jun by SP600125 in the postischemic gut. Mol Cell Biochem 347, 191–199 (2011). https://doi.org/10.1007/s11010-010-0628-x
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DOI: https://doi.org/10.1007/s11010-010-0628-x