Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes.
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 (BH(4)). We tested th...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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2009
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| _version_ | 1797081420305268736 |
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| author | Tie, L Li, X Wang, X Channon, K Chen, A |
| author_facet | Tie, L Li, X Wang, X Channon, K Chen, A |
| author_sort | Tie, L |
| collection | OXFORD |
| description | 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 (BH(4)). We tested the hypothesis that overexpression of GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme for de novo BH(4) 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 BH(4) 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 (O(2)(-)) level and inducible NOS (iNOS) activity. In STZ Tg-GCH mice, nitrite level and cNOS activity were potentiated and O(2)(-) level and iNOS activity were suppressed compared with STZ mice. Thus endothelium-specific BH(4) overexpression accelerates wound healing in type 1 diabetic mice by enhancing cNOS activity and suppressing oxidative stress. |
| first_indexed | 2024-03-07T01:14:12Z |
| format | Journal article |
| id | oxford-uuid:8e16bca2-925c-4837-8901-fcca37d321b0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:14:12Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:8e16bca2-925c-4837-8901-fcca37d321b02022-03-26T22:55:17ZEndothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8e16bca2-925c-4837-8901-fcca37d321b0EnglishSymplectic Elements at Oxford2009Tie, LLi, XWang, XChannon, KChen, ARefractory 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 (BH(4)). We tested the hypothesis that overexpression of GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme for de novo BH(4) 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 BH(4) 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 (O(2)(-)) level and inducible NOS (iNOS) activity. In STZ Tg-GCH mice, nitrite level and cNOS activity were potentiated and O(2)(-) level and iNOS activity were suppressed compared with STZ mice. Thus endothelium-specific BH(4) overexpression accelerates wound healing in type 1 diabetic mice by enhancing cNOS activity and suppressing oxidative stress. |
| spellingShingle | Tie, L Li, X Wang, X Channon, K Chen, A Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes. |
| title | Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes. |
| title_full | Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes. |
| title_fullStr | Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes. |
| title_full_unstemmed | Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes. |
| title_short | Endothelium-specific GTP cyclohydrolase I overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes. |
| title_sort | endothelium specific gtp cyclohydrolase i overexpression accelerates refractory wound healing by suppressing oxidative stress in diabetes |
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