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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/E525    most recent 00308.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Luo, J.-D. Articles by Chen, A. F. PubMed PubMed Citation Articles by Luo, J.-D. Articles by Chen, A. F.

Sonic hedgehog improves delayed wound healing via enhancing cutaneous nitric oxide function in diabetes

¹Department of Surgery, Hemostasis and Vascular Biology Research Institute and the McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine and Vascular Surgery Research, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; ²Department of Pharmacology and ³Guangzhou Institute of Cardiovascular Disease, Guangzhou Key Laboratory of Cardiovascular Disease, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; and ⁴Department of Pathophysiology, Guangdong Pharmaceutical University, Guangzhou, China

Submitted 13 May 2009 ; accepted in final form 10 June 2009

Sonic hedgehog (SHH) plays an important role in postnatal tissue repair. The present study tested the hypothesis that impaired SHH pathway results in delayed wound healing by suppressing cutaneous nitric oxide (NO) function in type 1 diabetes. Adult male C57/B6 mice and streptozotocin (STZ)-induced type 1 diabetic mice were used. Although cutaneous SHH and Patched-1 (Ptc-1 encoded by PTCH, PTCH 1) proteins were increased significantly on day 4 after wounding compared with day 0 in normal mice, both were decreased significantly in STZ-induced diabetic mice. Topical application of SHH restored wound healing delay in STZ-induced diabetic mice, with a concomitant augmentation of both cutaneous constitutive nitric oxide synthase (NOS) activity and nitrite level. The effects of SHH on wound healing and cutaneous NO function were markedly inhibited by SHH receptor inhibitor cyclopamine. After 24-h treatment in vitro, SHH (5–20 µg/ml) significantly increased cutaneous endothelial NOS protein expression, NOS activity and NO level in normal mice and STZ-induced diabetic mice in a concentration-dependent manner, an effect that was blunted by cyclopamine and NOS inhibitor N-nitro-L-arginine methyl ester. The phosphatidylinositol 3-kinase inhibitor LY-294002 significantly blunted the increase of NOS activity and NO level induced by SHH treatment in human umbilican vein endothelial cells. These results demonstrate that the SHH pathway is activated in a normal wound, and its reduction results in impaired NO function and wound healing in diabetes. Strategies aimed at augmenting the endogenous SHH pathway may provide an effective means in ameliorating delayed diabetic wound healing.

wound healing; sonic hedgehog; nitric oxide; diabetes