Effects of estrogen on ACE-Ang II-AT1 axis in ovariectomy and hypoxic pulmonary hypertension rats

Abstract

To explore the effects of estrogen (E2) on angiotensin converting enzyme-angiotensin II-angiotensin type 1 receptor (ACE-Ang II-AT1) axis in hypoxic pulmonary hypertension rats. A total of 60 healthy female Sprague-Dawdley (SD) rats were divided randomly into 6 groups (n = 10 each) of sham operation, pure ovariectomy (OVX), pure hypoxia,OVX+hypoxia,OVX+E2 and OVX+hypoxia+E2. Abdominal cavity was opened for sham operation group and bilateral ovaries were left intact without any other procedure. The pure OVX group underwent oophorectomy. The pure hypoxia group were placed into a low-oxygen environment (24 hour, 8 weeks). The OVX+hypoxia group were placed into a low-oxygen environment after bilateral oophorectomy. The OVX+E2 group received a subcutaneous injection of E2 (20 µg×kg(-1)×d(-1)) after bilateral oophorectomy. The OVX+hypoxia+E2 group had an injection of E2 and was placed into a low-oxygen environment after bilateral oophorectomy. The rats were feed continuously for 8 weeks to establish hypoxic pulmonary hypertension model. The mean pulmonary artery pressure (mPAP) was measured after bloodletting. Then right ventricle hypertrophy index (RVHI) and hematoxylin-eosin pulmonary artery remodeling (HPSR) were observed. And electron microscope was employed to observe pulmonary arteriolar ultrastructure. The methods of radio-immunity assay, ultraviolet spectroscopy, Western blot and reverse transcription PCR were used to measure the levels of CE,Ang II and AT1 in sera, lung and pulmonary artery. The vascular walls of pure hypoxia and OVX+hypoxia groups became thickened and lumen narrowed.mPAP and RVHI were (32.4 ± 2.2) mmHg (1 mmHg = 0.133 kPa),0.331 ± 0.032 and (37.9 ± 1.6) mmHg,0.433 ± 0.033. Both were significantly higher than those of Sham operation group ((12.6 ± 1.8) mmHg,0.233 ± 0.029) (both P < 0.05); the above parameters of OVX+Hypoxia+E2 group changed little. And mPAP ((26.1 ± 1.4) mmHg) was significantly higher than that in sham operation group (P < 0.05) while the difference in RVHI between OVX+ Hypoxia+ E2 (0.267 ± 0.040) and sham operation groups had no statistical significance (P > 0.05). Compared with Sham operation group, the expression levels of ACE,Ang II and AT1 in pure OVX, pure hypoxia and OVX+ hypoxia groups rose markedly (all P < 0.05).However, the OVX+E2 and OVX+ hypoxia+E2 groups had no obvious change (all P > 0.05). The intervention effect of E2 for hypoxic pulmonary hypertension may be partly mediated by the down-regulated expressions of ACE and AT1 in lung tissue resulting in the reduced activity of ACE-AngII-AT1 axis.