Pulmonary prostacyclin, synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension
Pulmonary prostacyclin, synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension
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DOI：
10.1172/jci5911
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发表时间：
1999-06-01
影响因子：
15.9
通讯作者：
Voelkel, NF
中科院分区：
文献类型：
--
作者：
Geraci, MW;Gao, BF;Voelkel, NF
前列环素合酶（PGIS）是前列环素（PGI（2））产生代谢途径中的最终关键酶。严重肺动脉高压患者的毛细血管前血管存在PGIS缺陷，但这种缺陷对肺血管重塑的重要性尚不清楚。我们假设PGIS的选择性肺部过度表达可能会阻止肺动脉高压的发生。为了研究这一假设，使用3.7 kb的人表面活性蛋白-C（SP-C）启动子和大鼠PGIS cDNA构建的选择性肺PGIS过表达的转基因小鼠。转基因小鼠（Tg（+））和同窝出生的非转基因小鼠（Tg（-））在17，000英尺的模拟海拔下生活5周，测量右心室收缩压（RVSP）。对肺进行组织学检查。Tg（+）小鼠产生的肺6-酮前列腺素F-1 α（PGF（1 α））水平是Tg（-）小鼠的2倍。在暴露于慢性低压缺氧后，Tg（+）小鼠的RVSP低于Tg（-）小鼠。肺组织学检查显示，与Tg（-）小鼠的血管壁肥大相比，Tg（+）小鼠的小动脉血管几乎正常。这些研究表明，Tg（+）小鼠暴露于慢性低压缺氧后，肺动脉高压的发展受到保护。我们的结论是，PGIS起着重要的作用，在修改肺血管反应慢性缺氧。这对严重肺动脉高压的发病机制和治疗具有重要意义。
Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway leading to prostacyclin (PGI(2)) production. Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels, but the importance of this deficiency for lung vascular remodeling remains unclear. We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension. To study this hypothesis, transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3.7-kb human surfactant protein-C (SP-C) promoter and the rat PGIS cDNA. Transgenic mice (Tg(+)) and nontransgenic littermates (Tg(-)) were subjected to a simulated altitude of 17,000 ft for 5 weeks, and right ventricular systolic pressure (RVSP) was measured. Histology was performed on the lungs. The Tg(+) mice produced 2-fold more pulmonary 6-keto prostaglandin F-1 alpha(PGF(1 alpha)) levels than did Tg(-) mice. After exposure to chronic hypobaric hypoxia, Tg(+) mice have lower RVSP than do Tg(-) mice. Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg(+) mice in comparison with vessel wall hypertrophy in the Tg(-) mice. These studies demonstrate that Tg(+) mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia. We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia. This has important implications for the pathogenesis and treatment of severe pulmonary hypertension.