Developmental Regulation of GTP-CH1 in the Porcine Lung and Its Relationship to Pulmonary Vascular Relaxation
Developmental Regulation of GTP-CH1 in the Porcine Lung and Its Relationship to Pulmonary Vascular Relaxation
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猪肺GTP-CH1的发育调控及其与肺血管舒张的关系
DOI：
10.1203/01.pdr.0000219301.19958.a0
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发表时间：
2006
影响因子：
3.6
通讯作者：
S. Haworth
中科院分区：
文献类型：
--
作者：
M. Nandi;J. Leiper;F. Arrigoni;A. Hislop;P. Vallance;S. Haworth
一氧化氮（NO）在新生儿出生后降低肺血管阻力中起重要作用。然而，在新生儿持续性肺动脉高压（PPHN）中，no介导的扩张功能不正常。gtp -环水解酶1 （GTP-CH1）是生物合成6r -l-红-5,6,7,8-四氢生物蝶呤（BH4）的限速酶，BH4是一氧化氮合酶（NOS）活性的重要辅助因子。亚理想水平的BH4可能导致NOS解偶联和随后产生有害的超氧阴离子。因此，我们研究了在猪肺内动脉中添加BH4和/或超氧化物歧化酶模拟物（MnTMPyP）对正常动物和猪PPHN模型的功能影响。我们研究了BH4的任何功能影响是否可以通过GTP-CH1表达的变化来解释。补充BH4可显著改善3 d龄和14 d龄健康动物的血管内皮依赖性松弛，而对年轻动物和成年动物的血管没有影响。GTP-CH1蛋白在第3天和第14天表达最低，提示此时BH4的表达率有限制。在猪PPHN模型中，单独补充BH4并不能改善动脉对乙酰胆碱的松弛反应。此外，GTP-CH1蛋白表达在不同年龄正常。然而，BH4和MnTMPyP联合治疗可恢复内皮功能。GTP-CH1在新生儿肺血管中受发育调节，这导致BH4在功能上的显著限制。虽然GTP-CH-1/BH4水平本身并不能解释PPHN中所见的严重内皮功能障碍，但通过补充BH4和淬火超氧化物来增加NO的生物利用度可能被证明是有益的。
Nitric oxide (NO) plays an important role in lowering pulmonary vascular resistance after birth. However, in persistent pulmonary hypertension of the newborn (PPHN) NO-mediated dilation is dysfunctional. GTP-cyclohydrolase 1 (GTP-CH1) is the rate-limiting enzyme for the biosynthesis of 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) an essential cofactor for nitric oxide synthase (NOS) activity. Suboptimal levels of BH4 may result in NOS uncoupling and the subsequent generation of harmful superoxide anions. We therefore investigated the functional effects of supplementing BH4 and/or a superoxide dismutase mimetic (MnTMPyP) in porcine intrapulmonary arteries from normal animals and from a porcine model of PPHN. We investigated whether any functional effects of BH4 could be explained by changes in GTP-CH1 expression. Supplementation of BH4 significantly improved endothelium-dependent relaxations in arteries from 3- and 14-d-old healthy animals, whereas no effect was seen in vessels from younger animals and adults. GTP-CH1 protein expression was lowest at 3 and 14 d, suggesting a rate limitation of BH4 at this time. BH4 supplementation alone did not improve the relaxant response to acetylcholine in arteries obtained in a porcine model of PPHN. Furthermore, GTP-CH1 protein expression was normal for age. However, co-treatment with both BH4 and MnTMPyP restored endothelial function. GTP-CH1 is developmentally regulated in the pulmonary vasculature of neonates and this results in a functionally significant limitation of BH4. Although GTP-CH-1/BH4 levels alone do not explain the profound endothelial dysfunction seen in PPHN, increasing NO bioavailability by supplementing BH4 and quenching superoxide may prove to be therapeutically beneficial.
DOI：
10.1016/s0301-2115(98)00321-2
发表时间：
1999-06-01
影响因子：
2.6
作者：
Heymann, MA
通讯作者：
Heymann, MA
影响因子：
15.9
作者：
Fagan, KA;Fouty, BW;Rodman, DM
通讯作者：
Rodman, DM