GTP cyclohydrolase I/BH4 pathway protects EPCs via suppressing oxidative stress and thrombospondin-1 in salt-sensitive hypertension.
GTP cyclohydrolase I/BH4 pathway protects EPCs via suppressing oxidative stress and thrombospondin-1 in salt-sensitive hypertension.
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GTP 环水解酶 I/BH4 通路通过抑制盐敏感性高血压中的氧化应激和血小板反应蛋白-1 来保护 EPC
DOI：
10.1161/hypertensionaha.110.160622
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发表时间：
2010-12
期刊：
影响因子：
--
通讯作者：
Chen AF
中科院分区：
文献类型：
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作者：
Xie HH;Zhou S;Chen DD;Channon KM;Su DF;Chen AF
内皮祖细胞（EPCs）在高血压中减少和功能障碍，与其死亡率呈负相关，但其机制尚不清楚。内皮型一氧化氮合酶（eNOS）对EPC的动员和功能有重要调节作用，但在盐敏感性高血压中，由于辅因子四氢生物蝶呤（BH 4）减少，eNOS发生解偶联。我们测试的假设，GTP环化水解酶I（GTPCH I），BH 4从头合成的限速酶，保护EPCs和其功能在脱氧皮质酮醋酸盐（DOCA）-盐小鼠。从野生型（WT）、WT DOCA盐、内皮特异性GTPCH转基因（Tg-GCH）、GTPCH转基因DOCA盐和BH 4缺陷型hph-1小鼠的外周血和骨髓中分离EPC。在WT DOCA盐和hph-1小鼠中，EPC显著减少，血管生成和粘附受损，在Tg-GCH DOCA盐小鼠中恢复。在WT DOCA盐和hph-1小鼠中，EPCs中的超氧化物（O2−）和一氧化氮（NO）水平分别升高和降低;在Tg-GCH DOCA盐小鼠中两者都得到了拯救。eNOS−/−/GCH+/−杂交小鼠证明，GTPCH保留了循环EPC数量，减少了EPC中的细胞内O2−，并改善了DOCA盐高血压中不依赖于eNOS的EPC功能障碍。内皮祖细胞分泌的血小板反应蛋白-1（TSP-1;一种有效的血管生成抑制剂）在WT DOCA盐和hph-1小鼠中升高，但DOCA盐Tg-GCH小鼠中未升高。在体外用BH 4、聚乙二醇超氧化物歧化酶（PEG-SOD）或N-硝基-L-精氨酸（L-NNA）处理WT DOCA-盐小鼠的EPC，显著增加NO，降低TSP-1和O2−水平。这些结果首次证明，GTPCH/BH 4通路至少部分地通过抑制TSP-1表达和氧化应激来严格调节DOCA盐高血压小鼠中的EPC数量和功能。
Endothelial progenitor cells (EPCs) are both reduced and dysfunctional in hypertension that correlates inversely with its mortality, but the mechanisms are poorly understood. Endothelial nitric oxide synthase (eNOS) critically regulates EPC mobilization and function but is uncoupled in salt-sensitive hypertension because of the reduced cofactor tetrahydrobiopterin (BH4). We tested the hypothesis that GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme of BH4 de novo synthesis, protects EPCs and its function in deoxycorticosterone acetate (DOCA)-salt mice. EPCs were isolated from peripheral blood and bone marrow of wild-type (WT), WT DOCA-salt, endothelial-specific GTPCH transgenic (Tg-GCH), GTPCH transgenic DOCA-salt, and BH4-deficient hph-1 mice. In WT DOCA-salt and hph-1 mice, EPCs were significantly decreased with impaired angiogenesis and adhesion, which were restored in Tg-GCH DOCA-salt mice. Superoxide (O2−) and nitric oxide (NO) levels in EPCs were elevated and reduced, respectively, in WT DOCA-salt and hph-1 mice; both were rescued in Tg-GCH DOCA-salt mice. eNOS−/−/GCH+/− hybrid mice demonstrated that GTPCH preserved the circulating EPC number, reduced intracellular O2− in EPCs, and ameliorated EPC dysfunction independent of eNOS in DOCA-salt hypertension. Secreted thrombospondin-1 (TSP-1; a potent angiogenesis inhibitor) from EPCs was elevated in WT DOCA-salt and hph-1 but not DOCA-salt Tg-GCH mice. In vitro treatment with BH4, polyethylene glycol-superoxide dismutase (PEG-SOD), or Nomega-nitro-L-arginine (L-NNA) significantly augmented NO and reduced TSP-1 and O2− levels from EPCs of WT DOCA-salt mice. These results demonstrated, for the first time, that the GTPCH/BH4 pathway critically regulates EPC number and function in DOCA-salt hypertensive mice, at least in part, via suppressing TSP-1 expression and oxidative stress.