Pulmonary hypertension in the newborn GTP cyclohydrolase I-deficient mouse.
Pulmonary hypertension in the newborn GTP cyclohydrolase I-deficient mouse.
复制标题
DOI：
10.1016/j.freeradbiomed.2011.09.012
复制
发表时间：
2011-12-15
影响因子：
7.4
通讯作者：
Vasquez-Vivar, Jeannette
中科院分区：
文献类型：
--
作者：
Belik, Jaques;McIntyre, Brendan A. S.;Enomoto, Masahiro;Pan, Jingyi;Grasemann, Hartmut;Vasquez-Vivar, Jeannette
四氢生物蝶呤（BH 4）是内皮型一氧化氮合酶（eNOS）活性的调节剂。缺乏水平导致eNOS解偶联，从一氧化氮（NO）转变为超氧化物生成。hph-1突变小鼠缺乏GTP-环化水解酶1（GTPCH 1）活性，导致BH 4组织含量低。成年hph-1小鼠具有肺动脉高压，但这种状况是否从出生就存在尚不清楚。因此，我们评估了新生动物肺动脉中膜厚度、生物喋呤含量（BH_4 + BH_2）、H_2O_2和eNOS、右心室/左心室+室间隔比值（RV/LV+室间隔）和近阻力肺动脉激动剂诱导的力以及内皮依赖性和非依赖性舒张。两种类型的生物蝶呤肺含量与年龄呈负相关，但与野生型动物相比，hph-1小鼠的生物蝶呤肺含量显著降低。根据RV/LV+隔膜判断，新生hph-1小鼠具有肺动脉高压，并且在两周13%氧气暴露后，两种类型的比率相似。在hph-1动物中，肺动脉激动剂诱导的力降低（P<0.01），并且没有观察到内皮依赖性或非依赖性血管舒张的类型依赖性差异。与野生型小鼠相比，hph-1小鼠肺组织中H2 O2含量增加，而eNOS表达减少（P<0.01）。与野生型小鼠相比，hph-1小鼠的肺动脉中膜厚度（血管重建的替代标记物）增加（P<0.01）。总之，我们的数据表明，肺动脉高压是目前从出生在GTPCH 1缺陷小鼠，而不是由于血管舒张受损，但继发于血管重塑。
Tetrahydrobiopterin (BH4) is a regulator of endothelial nitric oxide synthase (eNOS) activity. Deficient levels result in eNOS uncoupling with a shift from nitric oxide (NO) to superoxide generation. The hph-1 mutant mouse has deficient GTP-cyclohydrolase 1 (GTPCH1) activity resulting in low BH4 tissue content. The adult hph-1 mouse has pulmonary hypertension, but whether such condition is present from birth is not known. Thus, we evaluated newborn animals’ pulmonary arterial medial thickness, biopterins content (BH4+BH2), H2O2 and eNOS, right ventricle-to-left-ventricle+septum ratio (RV/LV+septum) and near-resistance pulmonary arteries agonist-induced force and endothelium-dependent and-independent relaxation. The biopterins lung content was inversely related to age for both types, but significantly lower in hph-1 mice, as compared to wild-type animals. As judged by the RV/LV+septum newborn hph-1 mice have pulmonary hypertension and following a two-week 13% oxygen exposure the ratio was similar in both types. The pulmonary arterial agonist-induced force was reduced (P<0.01) in hph-1 animals and no type-dependent difference in endothelium-dependent or –independent vasorelaxation was observed. When compared to wild-type mice, the H2O2 lung content was increased, whereas the eNOS expression decreased (P<0.01) in hph-1 animals. The pulmonary arterial medial thickness, a surrogate marker of vascular remodeling was increased (P<0.01) in hph-1 compared to wild-type mice. In conclusion, our data suggest that pulmonary hypertension is present from birth in the GTPCH1 deficient mice, not as a result of impaired vasodilation, but secondary to vascular remodeling.
登录
查看更多内容
影响因子：
7.4
作者：
Belik, J;Jankov, RP;Tanswell, AK
通讯作者：
Tanswell, AK
影响因子：
37.8
作者：
Nandi, M;Miller, A;Vallance, P
通讯作者：
Vallance, P
影响因子：
11.2
作者：
Hyland, K;Gunasekara, RS;Engle, T
通讯作者：
Engle, T
DOI：
10.1152/ajplung.00168.2009
发表时间：
2009-12-01
影响因子：
4.9
作者：
Belik, J.;Jerkic, M.;Letarte, M.
通讯作者：
Letarte, M.
影响因子：
7.4
作者：
Belik, Jaques;Stevens, Danielle;Jankov, Robert P.
通讯作者：
Jankov, Robert P.