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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/E1423    most recent 00150.2009v1 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 PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Tie, L. Articles by Chen, A. F. PubMed PubMed Citation Articles by Tie, L. Articles by Chen, A. F.

Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes

¹Department of Surgery, University of Pittsburgh School of Medicine and Vascular Surgery Research, Department of Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; Departments of ²Pharmacology and ³Physiology, School of Basic Medical Sciences, Peking University, Beijing, China; and ⁴Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom

Submitted 9 March 2009 ; accepted in final form 31 March 2009

Refractory wound is a severe complication that leads to limb amputation in diabetes. Endothelial nitric oxide synthase (eNOS) plays a key role in normal wound repair but is uncoupled in streptozotocin (STZ)-induced type 1 diabetes because of reduced cofactor tetrahydrobiopterin (BH₄). We tested the hypothesis that overexpression of GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme for de novo BH₄ synthesis, retards NOS uncoupling and accelerates wound healing in STZ mice. Blood glucose levels were significantly increased in both male endothelium-specific GTPCH I transgenic mice (Tg-GCH; via a tie-2 promoter) and wild-type (WT) littermates 5 days after STZ regimen. A full-thickness excisional wound was created on mouse dorsal skin by a 4-mm punch biopsy. Wound closure was delayed in STZ mice, which was rescued in STZ Tg-GCH mice. Cutaneous BH₄ level was significantly reduced in STZ mice vs. WT mice, which was maintained in STZ Tg-GCH mice. In STZ mice, constitutive NOS (cNOS) activity and nitrite levels were decreased compared with WT mice, paralleled by increased superoxide anion (O₂^–) level and inducible NOS (iNOS) activity. In STZ Tg-GCH mice, nitrite level and cNOS activity were potentiated and O₂^– level and iNOS activity were suppressed compared with STZ mice. Thus endothelium-specific BH₄ overexpression accelerates wound healing in type 1 diabetic mice by enhancing cNOS activity and suppressing oxidative stress.

tetrahydrobiopterin