The role of nitric oxide synthase isoforms and arginase in the pathogenesis of diabetic foot ulcers: possible modulatory effects by transforming growth factor beta 1

Aims/hypothesis. L-arginine, an amino acid involved in wound healing, is me tabolised by one of two pathways; nitric oxide synthase and arginase. If me tabolised by nitric oxide synthase, this can result in tissue destruction, or matrix deposition if metabolised by arginase. The aim therefore was to i nvestigate the role of these enzymes in the pathogenesis of diabetic foot u lcers. Methods. The activity, proteins by Western blot analysis and cellular distr ibution (using immunocytochemistry) of these enzymes were measured in diabe tic foot ulcers, diabetic skin and normal skin. Results. Total and inducible nitric oxide synthase (p<0.001) and endothelia l nitric oxide synthase were increased in diabetic ulcers compared with dia betic and normal skin and were associated with increased plasma nitrite con centrations in diabetic ulcers (p < 0.05). Inducible nitric oxide synthase was the major isoform, with the macrophage being the predominant cellular s ource. Similarly arginase activity was increased (p < 0.01) in diabetic ulc ers, The protein levels corroborated with the activity data, with the fibro blast being the major cellular source. The spatial and cellular distributio n of the two enzyme systems was distinct. Transforming growth factor-betal was decreased in diabetic ulcers in comparison with diabetic skin and norma l skin. Conclusion/interpretation. Increased nitric oxide synthese activity in diab etic foot ulcers may be responsible for the impaired healing in this diseas e. Furthermore, the increased activity of arginase could account for the ch aracteristic callus formation around these ulcers, In addition, the lower c oncentrations of transforming growth factor-betal in diabetic ulcers may ex plain the raised concentrations of nitric oxide in this condition.