Tetrahydrobiopterin oral therapy recouples eNOS and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs
Tetrahydrobiopterin oral therapy recouples eNOS and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs
复制标题
DOI：
10.1152/ajplung.00238.2016
复制
发表时间：
2016-10-01
影响因子：
4.9
通讯作者：
Fike, Candice D.
中科院分区：
文献类型：
--
作者：
Dikalova, Anna;Aschner, Judy L.;Fike, Candice D.
我们先前表明，在暴露于慢性缺氧期间发展肺动脉高压的新生仔猪具有减少的肺血管一氧化氮（NO）产生和内皮NO合酶（eNOS）解偶联的证据（Fike CD，Dikalova A，Kaplowitz MR，Cunningham G，Summar M，Aschner JL. Am J Respir Cell Mol Biol 53：255-264，2015）。四氢生物蝶呤（BH 4）是促进eNOS偶联的辅因子。目前的临床策略通常是在诊断肺动脉高压后开始治疗，而不是主动治疗。本研究的主要目的是确定在肺动脉高压发作后开始用口服BH 4化合物二盐酸沙丙蝶呤（沙丙蝶呤）治疗是否会重新偶联肺血管系统中的eNOS并改善慢性缺氧仔猪的疾病进展。研究了常氧（对照）和缺氧仔猪。一些缺氧仔猪在缺氧第3天开始接受口服沙丙蝶呤，并在另外7天的缺氧暴露中继续。放置导管进行血液动力学测量，并解剖肺动脉以评估eNOS二聚体与单体比率（eNOS偶联的测量）、NO产生和超氧化物（O-2（中心点-））产生。虽然高于常氧对照组，但沙丙蝶呤处理的缺氧仔猪的肺血管阻力低于未处理的缺氧仔猪。与eNOS再偶联一致，与未处理的缺氧动物相比，沙丙蝶呤处理的肺动脉中eNOS二聚体与单体的比率和NO产生更大，O-2（中心点）产生更少。当在疾病发作后开始时，口服沙丙蝶呤治疗至少部分地通过重新偶联新生仔猪肺血管中的eNOS来抑制慢性缺氧诱导的肺动脉高压。沙丙蝶呤补救治疗可能是一种有效的策略，以抑制肺动脉高压的进一步发展的新生儿患有慢性心肺疾病与长期缺氧发作。
We previously showed that newborn piglets who develop pulmonary hypertension during exposure to chronic hypoxia have diminished pulmonary vascular nitric oxide (NO) production and evidence of endothelial NO synthase (eNOS) uncoupling (Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Am J Respir Cell Mol Biol 53: 255-264, 2015). Tetrahydrobiopterin (BH4) is a cofactor that promotes eNOS coupling. Current clinical strategies typically invoke initiating treatment after the diagnosis of pulmonary hypertension, rather than prophylactically. The major purpose of this study was to determine whether starting treatment with an oral BH4 compound, sapropterin dihydrochloride (sapropterin), after the onset of pulmonary hypertension would recouple eNOS in the pulmonary vasculature and ameliorate disease progression in chronically hypoxic piglets. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received oral sapropterin starting on day 3 of hypoxia and continued throughout an additional 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios (a measure of eNOS coupling), NO production, and superoxide (O-2(center dot-)) generation. Although higher than in normoxic controls, pulmonary vascular resistance was lower in sapropterin-treated hypoxic piglets than in untreated hypoxic piglets. Consistent with eNOS recoupling, eNOS dimer-to-monomer ratios and NO production were greater and O-2(center dot-) generation was less in pulmonary arteries from sapropterin-treated than untreated hypoxic animals. When started after disease onset, oral sapropterin treatment inhibits chronic hypoxia-induced pulmonary hypertension at least in part by recoupling eNOS in the pulmonary vasculature of newborn piglets. Rescue treatment with sapropterin may be an effective strategy to inhibit further development of pulmonary hypertension in newborn infants suffering from chronic cardiopulmonary conditions associated with episodes of prolonged hypoxia.