[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]

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.