Uncoupling of eNOS causes superoxide anion production and impairs NO signaling in the cerebral microvessels of hph-1 mice.
Uncoupling of eNOS causes superoxide anion production and impairs NO signaling in the cerebral microvessels of hph-1 mice.
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DOI：
10.1111/j.1471-4159.2012.07872.x
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发表时间：
2012-09
影响因子：
4.7
通讯作者：
Katusic ZS
中科院分区：
文献类型：
--
作者：
Santhanam AV;d'Uscio LV;Smith LA;Katusic ZS
在本研究中，我们使用GTP环水解酶i缺陷小鼠，即。为了验证脑微血管中四氢生物terin （BH4）的缺失导致内皮型一氧化氮合酶（eNOS）解偶联，导致超氧阴离子产生增加和内皮型一氧化氮（NO）信号传导抑制的假设。纯合突变体（hph-1-/-）和杂合突变体（hph-1+/-）小鼠均表现出GTP环水解酶I活性降低和BH4的生物利用度降低。在hph-1+/-和hph-1-/-小鼠的脑微血管中，添加BH4或NOS抑制剂- L-NAME可抑制超氧阴离子的产生，表明eNOS解偶联。3-硝基酪氨酸表达显著升高，NO生成和cGMP水平显著降低。抗氧化酶CuZnSOD、MnSOD和过氧化氢酶的表达不受eNOS解偶联的影响。雄性和雌性小鼠微血管中BH4水平的降低、超氧阴离子产生的增加以及NO信号的抑制没有差异。我们的研究结果首次证明，无论性别如何，BH4生物利用度降低都会导致eNOS解偶联，增加超氧阴离子的产生，抑制eNOS/cGMP信号传导，并在脑微血管中施加显著的氧化应激。
In the present study, we used the GTP cyclohydrolase I-deficient mice, ie., hph-1 mice, to test the hypothesis that the loss of tetrahydrobiopterin (BH4) in cerebral microvessels causes endothelial nitric oxide synthase (eNOS) uncoupling resulting in increased superoxide anion production and inhibition of endothelial nitric oxide (NO) signaling. Both homozygous mutant (hph-1-/-) and heterozygous mutant (hph-1+/- mice) demonstrated reduction in GTP cyclohydrolase I activity and reduced bioavailability of BH4. In the cerebral microvessels of hph-1+/- and hph-1-/- mice, increased superoxide anion production was inhibited by supplementation of BH4 or NOS inhibitor - L-NAME, indicative of eNOS uncoupling. Expression of 3-nitrotyrosine was significantly increased, while NO production and cGMP levels were significantly reduced. Expressions of antioxidant enzymes namely CuZnSOD, MnSOD and catalase were not affected by uncoupling of eNOS. Reduced levels of BH4, increased superoxide anion production as well as inhibition of NO signaling were not different between the microvessels of male and female mice. The results of our study are the first to demonstrate that, regardless of gender, reduced BH4 bioavailability causes eNOS uncoupling, increases superoxide anion production, inhibits eNOS/cGMP signaling, and imposes significant oxidative stress in the cerebral microvasculature.
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影响因子：
4.7
作者：
Canevari, L;Land, JM;Heales, SJR
通讯作者：
Heales, SJR
DOI：
10.1152/ajpheart.00079.2002
发表时间：
2002-10-01
影响因子：
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作者：
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Landmesser, U;Dikalov, S;Harrison, DG
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作者：
Faraci, FM;Lamping, KG;Didion, SP
通讯作者：
Didion, SP
DOI：
10.1152/ajpheart.01215.2003
发表时间：
2004-09-01
影响因子：
4.8
作者：
Andresen, JJ;Faraci, FM;Heistad, DD
通讯作者：
Heistad, DD