INTESTINE

Arginine stimulates intestinal cell migration through a focal adhesion kinase dependent mechanism

J M Rhoads¹, W Chen², J Gookin³, G Y Wu⁴, Q Fu¹, A T Blikslager³, R A Rippe⁵, R A Argenzio³, W G Cance⁶, E M Weaver⁷, L H Romer⁸

¹ Department of Pediatrics, and Center in Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA, and Department of Pediatrics, Ochsner Clinic Foundation, New Orleans, Louisiana, USA
² Department of Pediatrics, and Center in Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA
³ Center in Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA, and Departments of Anatomy, Physiological Sciences, and Radiology and Clinical Sciences, North Carolina State University College of Veterinary Medicine, Raleigh, North Carolina, USA
⁴ Faculty of Nutrition, Texas A&M University, College Station, Texas, USA
⁵ Department of Medicine, and Center in Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA
⁶ Department of Surgery, University of Florida, Gainesville, Florida, USA
⁷ LG Laboratories, Ames, Iowa, USA
⁸ Departments of Anesthesiology, Cell Biology, and Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA

Correspondence to:
Correspondence to:
Dr J M Rhoads
Pediatric Gastroenterology, Ochsner for Children, 1514 Jefferson Hwy, New Orleans, LA 70121, USA; mrhoads{at}ochsner.org

Background: L-Arginine is a nutritional supplement that may be useful for promoting intestinal repair. Arginine is metabolised by the oxidative deiminase pathway to form nitric oxide (NO) and by the arginase pathway to yield ornithine and polyamines.

Aims: To determine if arginine stimulates restitution via activation of NO synthesis and/or polyamine synthesis.

Methods: We determined the effects of arginine on cultured intestinal cell migration, NO production, polyamine levels, and activation of focal adhesion kinase, a key mediator of cell migration.

Results: Arginine increased the rate of cell migration in a dose dependent biphasic manner, and was additive with bovine serum concentrate (BSC). Arginine and an NO donor activated focal adhesion kinase (a tyrosine kinase which localises to cell matrix contacts and mediates ß1 integrin signalling) after wounding. Arginine stimulated cell migration was dependent on focal adhesion kinase (FAK) signalling, as demonstrated using adenovirus mediated transfection with a kinase negative mutant of FAK. Arginine stimulated migration was dependent on NO production and was blocked by NO synthase inhibitors. Arginine dependent migration required synthesis of polyamines but elevating extracellular arginine concentration above 0.4 mM did not enhance cellular polyamine levels.

Conclusions: These results showed that L-arginine stimulates cell migration through NO and FAK dependent pathways and that combination therapy with arginine and BSC may enhance intestinal restitution via separate and convergent pathways.

Keywords: arginine; intestinal cell migration; nitric oxide; focal adhesion kinase; polyamines

Abbreviations: ARG, L-arginine; BSC, bovine serum concentrate; DFMO, difluoromethyl-ornithine; Deta-NONOate, 3,3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene; DMEM, Dulbecco’s modified Eagle’s medium; FAK, focal adhesion kinase; FBS, fetal bovine serum; iNOS, inducible nitric oxide synthase; IGF-1, insulin-like growth factor 1; L-Nil, L-N6(1-iminoethyl)lysine; NEC, necrotising enterocolitis; NMMA, L-N^G-monomethyl arginine; NO, nitric oxide; NOS, nitric oxide synthase; ODC, ornithine decarboxylase; PBS, phosphate buffered saline; PUT, putrescine; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; TGF-ß, transforming growth factor ß

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