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Endothelial‐specific BH4 expression accelerates refractory wound healing by enhancing eNOS activity and suppressing oxidative stress in type 1 diabetes
Author(s) -
Tie Lu,
Marrotte Eric J.,
Chan Keith M.,
Chen Alex F.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1226.8
Subject(s) - enos , streptozotocin , endocrinology , medicine , wound healing , oxidative stress , diabetes mellitus , chemistry , nitric oxide , nitric oxide synthase , surgery
Background: Refractory wound is a severe complication in diabetes that leads to limb amputation, but the mechanisms are poorly understood. eNOS plays a key role in normal wound repair, but is uncoupled in streptozotocin (STZ)‐induced type 1 diabetes due to reduced cofactor BH4. We tested the hypothesis that GTP cyclohydrolase I (GTPCH), the rate‐limiting enzyme of BH4 synthesis, retards eNOS uncoupling with accelerated wound healing in STZ mice. Methods and Results: Blood glucose levels were significantly increased in both male GTPCH transgenic mice (Tg‐GCH) and the 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. The rate of wound closure in STZ mice was delayed by 18.48% compared to normal WT mice, which was rescued in STZ Tg‐GCH mice by an average of 8.48% (n=3–5, p <0.05). HPLC analysis showed that cutaneous BH4 level was significantly reduced in STZ mice vs. WT mice (n=4–5, p<0.05), which was maintained in STZ Tg‐GCH mice. In STZ mice, cutaneous eNOS activity and nitrite level were decreased compared to WT mice, paralleled by increased superoxide (O 2 − ) level. In STZ Tg‐GCH mice, nitrite level was potentiated and O 2 − level was suppressed compared to STZ mice. Conclusion: Endothelial‐specific BH4 overexpression accelerates wound healing in STZ type 1 diabetes mice by enhancing eNOS activity and suppressing oxidative stress.