Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse
Pulmonary hypertension in a GTP-cyclohydrolase 1-deficient mouse
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DOI：
10.1161/01.cir.0000163268.32638.f4
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发表时间：
2005-04-26
期刊：
影响因子：
37.8
通讯作者：
Vallance, P
中科院分区：
文献类型：
--
作者：
Nandi, M;Miller, A;Vallance, P
背景-GTP-环化水解酶1（GTP-CH 1）催化从头产生四氢生物蝶呤（BH（4））的第一步，BH（4）是一氧化氮合酶（NOS）的辅因子。高苯丙氨酸血症突变小鼠（hph-1）显示GTP-CH 1活性降低90%。BH（4）减少会降低NOS活性，并可能导致内皮功能障碍，越来越多的证据表明NOS通路的功能障碍可能与肺动脉高压有关。该研究的目的是调查是否减少BH（4）在hph-1小鼠的结果在肺动脉高压phenotype.Methods和结果-心脏，肺，肾和测量全身和右心室血压的形态学特征进行了hph-1和野生型小鼠。同时测定BH（4）和NO（x）水平。Hph-1小鼠的NO（x）和BH（4）水平显著降低，与先前的研究结果一致。形态学和体内数据均表明肺性而非全身性高血压表型。我们观察到右心室-左心室加室间隔比率增加，仅归因于右心室质量增加、肺阻力血管中平滑肌内侧面积增加和体内右心室压力显著升高。左心室质量和体循环压力之间没有显著差异，在野生型和hph-1之间的肾脏切片中没有观察到体循环高血压的证据。结论-本研究表明GTP-CH 1/BH（4）缺陷的小鼠显示肺动脉高压而不是体循环高血压表型。
Background - GTP-cyclohydrolase 1 (GTP-CH1) catalyzes the first step for the de novo production of tetrahydrobiopterin (BH(4)), a cofactor for nitric oxide synthase (NOS). The hyperphenylalaninemic mutant mouse (hph-1) displays a 90% reduction in GTP-CH1 activity. Reduced BH(4) decreases NOS activity and may lead to endothelial dysfunction, and there is increasing evidence that a dysfunction of the NOS pathway may be implicated in pulmonary hypertension. The aim of the study was to investigate whether reduced BH(4) in the hph-1 mouse results in a pulmonary hypertensive phenotype.Methods and Results - Morphological characterization of the heart, lung, and kidney and measurements of systemic and right ventricular blood pressures were performed in both hph-1 and wild-type mice. BH(4) and NO(x) levels were also measured. Hph-1 mice had significantly lower NO(x) and BH(4) levels, consistent with previous findings. Both morphological and in vivo data were indicative of a pulmonary but not systemic hypertensive phenotype. We observed increased right ventricle - left ventricle plus septum ratios attributable only to an increase in right ventricular mass, increased smooth muscle medial area in pulmonary resistance vessels, and significantly higher right ventricular pressures in vivo. There were no significant differences between left ventricular masses and systemic pressures, and there was no observed evidence of systemic hypertension in kidney sections between wild-type and hph-1.Conclusions - This study demonstrates that mice deficient in GTP-CH1/BH(4) display a pulmonary hypertensive but not systemic hypertensive phenotype.