Refractory wound healing and FoxO1/iNOS pathway in type 1 diabetes (1142.3)

Abstract

Aims/hypothesis Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens. The present study was designed to determine the role of FoxO1/iNOS pathway and effect of the soy isoflavone genistein on diabetic wound healing.Methods Streptozotocin (STZ)‐induced type 1 diabetic mice with full‐thickness excisional wounds given intragastrically 1 and 3 mg/kg/day of iNOS selective inhibitor (L‐NIL) or received 0.2, 1 and 5 mg/kg/day of genistein via subcutaneous injection.Results In diabetic wound tissues, the inducible nitric oxide synthase (iNOS) was activated, silent information regulator 1 (SIRT1) and forkhead box O transcription factor 1 (FoxO1) were elevated. Genistein administration prevented increased iNOS activity and attenuated diabetic cutaneous SIRT1 and FoxO1 levels in a dose‐dependent manner. Diabetic conditions significantly increased superoxide anion (O2.‐) production, nitrotyrosine formation, and decreased nitrite levels in wound tissues. L‐NIL and genistein treatments normalized the elevated O2.‐ production, nitrotyrosine formation and reversed the attenuated nitrite level. L‐NIL and genistein dose‐dependently rescued the delay of wound closure in diabetic mice. Five mg/kg/day of genistein treatment significantly increased the mean perfusion rate, and in vitro treatment with genistein protected against high glucose‐induced impairment of capillary tube formation in cultured endothelial cells.Conclusions/interpretation FoxO1/iNOS signaling may contribute to the delayed wound healing in type 1 diabetes. Genistein could rescue the impaired wound healing and improved wound angiogenesis in type 1 diabetic mice, at least in part, by suppression of FoxO1, iNOS activity and oxidative stress.Grant Funding Source: This work was supported by the NSFC and Beijing Higher Education Young Elite Teacher Project