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Enteral arginine modulates inhibition of AP-1/c-Jun by SP600125 in the postischemic gut

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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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Acknowledgment

This study was supported by grants from the National Institutes of Health (RO1GM077282).

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Authors and Affiliations

  1. Department of Surgery, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 4.284, Houston, TX, 77030, USA

    Kechen Ban & Rosemary A. Kozar

  2. Department of Surgery, Methodist Hospital, Houston, TX, 77030, USA

    Rachel Santora

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  1. Kechen Ban
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  2. Rachel Santora
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  3. Rosemary A. Kozar
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Correspondence to Rosemary A. Kozar.

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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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