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BH4 protects endothelial progenitor cell number and function via suppressing thrombospondin‐1 expression in salt‐sensitive hypertension
Author(s) -
Xie HeHui,
Du YanHua,
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.964.8
Subject(s) - endocrinology , enos , medicine , flow cytometry , western blot , tetrahydrobiopterin , thrombospondin 1 , chemistry , angiogenesis , gtp cyclohydrolase i , microbiology and biotechnology , nitric oxide , biology , biochemistry , nitric oxide synthase , gene
Background: Endothelial progenitor cells (EPC) are both reduced and dysfunctional in hypertension that correlates inversely with its mortality, but the mechanisms are poorly understood. eNOS regulates EPC mobilization and function, but is uncoupled in DOCA‐salt hypertension due to reduced cofactor BH4. We tested the hypothesis that GTP cyclohydrolase I (GTPCH), the rate‐limiting enzyme of BH4 synthesis, protects EPC and its function in DOCA‐salt mice. Methods and Results: EPC were isolated from peripheral blood and bone marrow of wild‐type (WT), GTPCH transgenic (Tg‐GCH) and BH4 deficient hph‐1 mice. In WT DOCA‐salt and hph‐1 mice, EPC number was significantly reduced (flow cytometry and fluorescence microscopy, n=7–12, p<0.01), which was rescued in DOCA‐salt Tg‐GCH mice (n=5–8). Compared with WT Sham mice, both EPC adhesion and angiogenesis functions were impaired in WT DOCA‐salt and hph‐1 mice, which were reversed in DOCA‐salt Tg‐GCH mice. Superoxide level (DHE flow cytometry) in EPC was augmented in WT DOCA‐salt and hph‐1 mice, which was blunted in DOCA‐salt Tg‐GCH mice. Western blot showed that the secreted thrombospondin‐1 (TSP‐1, a key inhibitor of EPC function) from EPC was elevated in WT DOCA‐salt and hph‐1 but not in DOCA‐salt Tg‐GCH mice, which was prevented by NOS inhibitor L‐NNA. Conclusion: GTPCH/BH4 pathway protects EPC and its functions in DOCA‐salt hypertension b suppressing TSP‐1 expression.