[缺氧诱导因子-1α、内皮素-1及诱导型一氧化氮合酶在新生大鼠缺氧性肺动脉高压发病机制中的作用]

[Effect of hypoxia-inducible factor-1α, endothelin-1 and inducible nitric oxide synthase in the pathogenesis of hypoxia-induced pulmonary hypertension of the neonatal rats].

作者信息

Sang Kui, Zhou Ying, Li Ming-xia

机构信息

Department of Neonatology, First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China.

出版信息

Zhonghua Er Ke Za Zhi. 2012 Dec;50(12):919-24.

PMID:23324150

Abstract

OBJECTIVE

To study the effect of hypoxia-inducible factor-1α (HIF-1α) in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH) of the neonatal rats through the study on the expression level of HIF-1α and its regulation factors: endothelin-1 (ET-1) and inducible nitric oxide synthase (iNOS) in blood serum and lung tissue.

METHODS

To make an HPH model of neonatal rats, 120 newborn Wistar rats were divided at random into two groups: HPH group and the regular oxygen controlled group with the same birthday. The rats of the two groups were put in the condition of hypoxia for 3, 5, 7, 10, 14, 21 days and then 10 rats of HPH group and control group were picked up, their mean pulmonary arterial pressure (mPAP), serum HIF-1α, and iNOS, and ET-1 content were tested, and finally their lung tissue was taken after they were sacrificed and the expression level of the gene mRNA of HIF-1α, iNOS and ET-1.

RESULTS

(1) The rats experienced hypoxia for 3, 5, 7, 10, 14 or 21 days had an increasing mPAP: [8.47 ± 1.45, 10.04 ± 1.69, 10.89 ± 2.97, 16.96 ± 1.97, 13.01 ± 1.93, 21.04 ± 2.13 (mm Hg)], which had a significant differences compared with control groups [5.11 ± 1.06, 8.12 ± 1.11, 8.77 ± 0.92, 12.23 ± 1.78, 8.89 ± 0.89, 11.09 ± 1.64 (mm Hg)] (P < 0.05). (2) The rats in hypoxia group had a higher serum HIF-1α [0.83 ± 0.07, 0.84 ± 0.17, 0.97 ± 0.13, 1.10 ± 0.30, 0.92 ± 0.19 (pg/nmol)] than the control group [0.26 ± 0.20, 0.37 ± 0.16, 0.44 ± 0.18, 0.41 ± 0.23, 0.66 ± 0.18 (pg/nmol)] as they experienced hypoxia for 3, 5, 7, 10, and 14 days (P < 0.05); HIF-1α mRNA expression in lung tissue (1.301 ± 0.47, 1.032 ± 0.47, 1.453 ± 0.76) was also significantly higher than that of the control group (0.231 ± 0.26, 0.425 ± 0.59, 0.692 ± 0.13) (P < 0.05); serum ET-1 levels [51.50 ± 3.19, 44.1 ± 10.81, 56.85 ± 9.10, 52.91 ± 9.59, 51.16 ± 8.87, 50.21 ± 10.41 (pg/nmol)] were clearly higher than that of the control group [9.04 ± 2.85, 21.70 ± 8.78, 19.63 ± 9.66, 18.30 ± 7.32, 19.69 ± 5.92, 16.88 ± 6.14 (pg/nmol)] (P < 0.01); ET-1 mRNA expression in lung tissue (0.037 ± 0.018) was significantly increased after 3-day hypoxia as compared with control group (0.006 ± 0.004) (P < 0.05). Serum content of iNOS (5.62 ± 0.79) µmol/L was significantly higher than the control group (1.63 ± 0.67) µmol/L (P < 0.05) after a 3-day hypoxia, but there was no significant difference after a hypoxia for 5, 7 or 10 days, compared with the control group (P > 0.05), and the content of serum iNOS after hypoxia for 14 or 21 days (4.56 ± 0.96, 5.86 ± 1.76) µmol/L was lower than that of the control group (10.35 ± 1.99, 8.44 ± 2.76) µmol/L (P < 0.05). iNOS mRNA expression in lung tissue (0.035 ± 0.024, 0.332 ± 0.198, 0.527 ± 0.098) significantly increased after hypoxia for 3, 5 or 7 days as compared with the control group (0.005 ± 0.0001, 0.008 ± 0.002, 0.040 ± 0.012) (P < 0.05).

CONCLUSION

As an initial factor, low oxygen made HIF-1α, ET-1 and iNOS expression raised in the pathogenesis of HPH of the neonatal rats and causedn a imbalance of ET-1 and NO. HIF-1α, ET-1 and iNOS altogether contributed to the occurrence and development of HPH in neonatal rats.

摘要

目的

通过研究新生大鼠血清及肺组织中缺氧诱导因子-1α（HIF-1α）及其调节因子内皮素-1（ET-1）和诱导型一氧化氮合酶（iNOS）的表达水平，探讨HIF-1α在新生大鼠缺氧性肺动脉高压（HPH）发病机制中的作用。

方法

将120只新生Wistar大鼠随机分为两组：HPH组和同日龄正常氧对照组，制作新生大鼠HPH模型。两组大鼠分别置于缺氧环境3、5、7、10、14、21天，然后分别从HPH组和对照组中选取10只大鼠，检测其平均肺动脉压（mPAP）、血清HIF-1α、iNOS和ET-1含量，最后处死大鼠取肺组织，检测HIF-1α、iNOS和ET-1基因mRNA的表达水平。

结果

（1）缺氧3、5、7、10、14或21天的大鼠mPAP升高：[8.47±1.45，10.04±1.69，10.89±2.97，16.96±1.97，13.01±1.93，21.04±2.13（mmHg）]，与对照组[5.11±1.06，8.12±1.11，8.77±0.92，12.23±1.78，8.89±0.89，11.09±1.64（mmHg）]相比有显著差异（P<0.05）。（2）缺氧组大鼠在缺氧3、5、7、10和14天时血清HIF-1α[0.83±0.07，0.84±0.17，0.97±0.13，1.10±0.30，0.92±0.19（pg/nmol）]高于对照组[0.26±0.20，0.37±0.16，0.44±0.18，0.41±0.23，0.66±0.18（pg/nmol）]（P<0.05）；肺组织中HIF-1α mRNA表达（1.301±0.47，1.032±0.47，1.453±0.76）也显著高于对照组（0.231±0.26，0.425±0.59，0.692±0.13）（P<0.05）；血清ET-1水平[51.50±3.19，44.1±10.81，56.85±9.10，52.91±9.59，51.16±8.87，50.21±10.41（pg/nmol）]明显高于对照组[9.04±·2.85，21.70±8.78，19.63±9.66，18.30±7.32，19.69±5.92，16.88±6.14（pg/nmol）]（P<0.01）；缺氧3天后肺组织中ET-1 mRNA表达（0.037±0.018）与对照组（0.006±0.004）相比显著增加（P<0.05）。缺氧3天后血清iNOS含量（5.62±0.79）μmol/L显著高于对照组（1.63±0.67）μmol/L（P<0.05），但缺氧5、7或10天后与对照组相比无显著差异（P>0.05），缺氧14或21天后血清iNOS含量（4.56±0.96，5.86±1.76）μmol/L低于对照组（10.35±1.99，8.44±2.76）μmol/L（P<0.05）。缺氧3、5或7天后肺组织中iNOS mRNA表达（0.035±0.024，0.332±0.198，0.527±0.098）与对照组（0.005±0.0001，0.008±0.002，0.040±0.012）相比显著增加（P<0.05）。