The Significance Of Ang Ⅱ Signal Pathway And AQP5 Expression In The Lung Of Patients With Congenital Heart Diseases And Pulmonary Arterial Hypertension

Background and ObjectThe pathogenesis of pulmonary hypertension with congenital heart disease has not been elucidated completely due to its complexity and numerous factors involved. Renin-angiotensin system (RAS) plays an important role in maintaining cardiovascular function stable, water-electrolyte balance, cell growth, and fibrous degeneration of tissues. Furthermore, it was of great importance to regulate pulmonary circulation. Angiotensin II (Ang II) was the main ingredient of RAS. Its physio-function was mainly mediated through angiotensin II receptor type 1 (AT1). The role played by Ang II and AT1 in general circulation has been detected clearly, and a consensus concerning its vital function in the process of myocardial apoptosis and remodeling has been achieved. However, few studies on its role in the genesis and development of hypertensive pulmonary vascular remodeling have been reported. Aquaporin (AQPs) was a group of cellular membrane transport protein related with water permeation. AQP5 was distributed in the respiratory epithelia from airtube to pulmonary alveolus, and involved in epithelial barrier function, membrane permeability, and water homeostasis in the respiratory epithelia.This study was designed to explore the significance of AngⅡsignal pathway and AQP5 expression in the lung of patients with congenital heart diseases and pulmonary hypertension, and to provide fresh perspective and treatment target for cure and precaution against CHD with PH.Methods:1.The study was under the guidance of the medical ethical principles. 40 cases of patients with ventricular septal defect repair were selected. The patients were divided into 4 groups according to mean pulmonary arterial pressure (mPAP) measured by pre-operative Doppler-echocardiogram: group 1 with mPAP≤25mmHg; group 2A with mPAP26～35mmHg; group 2B with mPAP36～45mmHg;group 2C with mPAP≥46mmHg). There were 10 patients in each group.2.Arterial blood of the patients in the 4 groups was sampled before the operation and AngⅡcontent in serum was measured by radio-immunity method.3.Lung tissues of the patients in each group was sampled during the operation. AT1 expression was measured by immunohistochemistry, Phosphorylated STAT1 expression was detected by Western blot, The activity of NF-κB ascertained by EMSA. AQP5 mRNA expression was inspected by RT-PCR, AQP5 protein expression was checked-out by Western blot.4.Eight patients with severe PAH were treated with oral Captopril pre-operative for two weeks,. The effects of Captopril on the Ang II signal pathway and expression of AQP5 in the lung of patients with severe PAH were investigated.Results:1.With the increase of pulmonary arterial pressure, Ang II contents in serum of all the patients tended to rise. Ang II contents in serum of Group 2A, 2B and 2C were remarkably higher than that of Group 1 (p<0.05).2.With the increase of pulmonary arterial pressure, AT1 expressions in the patients'lung tissues rose gradually. AT1 expressions of group 2A, 2B and 2C were remarkably higher than that of group 1 (p<0.05). Phosphorylated STAT1 contents in patients'lung tissues rose gradually. Phosphorylated STAT1 contents of group 2A, 2B and 2C were remarkably higher than that of group 1 (p<0.05). The activity of NF-κB in patients'lung tissues decrease gradually. The activity of NF-κB in group 2A, 2B, and 2C were remarkably lower than that of group 1 (p<0.05). AQP5 mRNA and protein expression in patients'lung tissues decline gradually. AQP5 mRNA and protein expression in group 2A, 2B and 2C were remarkably lower than that of group 1 (p<0.05).3.Captopril could inhibit the activity of Ang II signal pathway and promote the expression of AQP5 mRNA and protein in the lung tissue of patients with pulmonary arterial hypertension. The difference was significant between the control group and treatment group (p<0.05). Conclusion:1.Ang II signal pathway of patients with congenital heart disease changed remarkably with the increase of pulmonary arterial pressure. The serum Ang II level elevated. The AT1 expressions and phosphorylated STAT1 contents increased. But the activity of NF-κB decreased. The results implicated that the increasing activity of Ang II signal pathway play an important role in the pathogenesis in the genesis and development of secondary pulmonary arterial hypertension.2.With the increase of pulmonary arterial pressure, AQP5 mRNA expression and AQP5 protein content gradually decreased in the lung tissues of the patients with congenital heart disease. The results implicated that there would be some disfunction of water balance ability of alveolar epithelium in lung tissues of the patients with pulmonary hypertension. It was probably the important mechanism for congenital heart disease with pulmonary hypertension tends to pneumonedema post operation.3.In the patients with severe pulmonary hypertension, oral captopril pre-operative inhibited the activity of Ang II signal pathway of Ang II levels, AT1 expressions, phosphorylative STAT1 contents. At the same time , the NF-κB activity increased, and AQP5 mRNA and AQP5 protein expression up-regulated in the lung tissues of the patients. The results recommended that the therapy targeted on Ang II signal pathway and AQP5 expression would improve the pulmonary vascular remodeling and water homeostasis in the respiratory epithelia.