[骨形态发生蛋白-2在缺氧性肺动脉高压发病机制中的作用]

[The role of bone morphogenetic protein-2 in the pathogenesis of hypoxic pulmonary hypertension].

作者信息

Yang Ying, Cheng De-Yun, Fan Li-Li, Yang Yan-Juan, Mu Mao, Chen Wen-Bin

机构信息

Department of Respiratory Medicine, West China Hospital of Sichuan University, Chengdu 610041, China.

出版信息

Zhonghua Jie He He Hu Xi Za Zhi. 2007 Sep;30(9):662-6.

PMID:18070548

Abstract

OBJECTIVE

To investigate the change of bone morphogenetic protein-2 (BMP-2) in the lung tissues of rats with hypoxic pulmonary hypertension (HPH) and the role of BMP in the apoptosis of endothelial cells exposed to hypoxia.

METHODS

Twenty male Wistar rats were randomly divided into two groups, the HPH group and the control group, 10 rats in each group. The HPH model was established by placing the rats in an isobaric chamber [O(2) = (10 +/- 0.5)%] for three weeks. The distribution of BMP-2 in pulmonary tissues was observed by using streptavidin peroxidase method (SP), and the morphologic changes of pulmonary arterioles and the integrated optical density (IA) of BMP-2 were determined by image analysis. The effect of Noggin (a blocking agent of BMP) on the apoptosis of hypoxic cultivated human umbilical vein endothelial cells (HUVEC) was assayed by flow cytometers.

RESULTS

Compared to the control group, pulmonary artery hypertension was evident in the hypoxic rats: mPAP was 16.3 +/- 0.5 mm Hg (1 mm Hg = 0.133 kPa) vs (29.5 +/- 0.9) mm Hg, P < 0.01. In the hypoxic rats, the pulmonary arteriolar wall thickened significantly; WT% was (16 +/- 5)% vs (27 +/- 7)%, and WA% was (54 +/- 11)% vs (80 +/- 8)%, both P < 0.01. The distribution of BMP-2 was mainly in the pulmonary arteriolar walls. The IA of BMP-2 significantly increased (6124 +/- 1199 vs 13 463 +/- 5755, P < 0.01), and showed a positive linear relationship to WT% and WA% respectively (WT%: r = 0.744 P < 0.01; WA%: r = 0.693 P < 0.01). Hypoxia induced apoptosis of HUVEC; the apoptosis rate was increased from 6% to 14% and 25% after exposure to hypoxia for 24 h and 48 h respectively. The HUVEC apoptosis rate induced by hypoxia was reduced by Noggin to 11.91% (24 h) and 15.01% (48 h).

CONCLUSIONS

Chronic hypoxia induced an increased expression of BMP-2, and a blocking agent of BMP inhibited the apoptosis of endothelial cells induced by hypoxia. It suggests that BMP may play an important role in the pathogenesis of hypoxic pulmonary hypertension.

摘要

目的

探讨低氧性肺动脉高压（HPH）大鼠肺组织中骨形态发生蛋白-2（BMP-2）的变化以及BMP在缺氧诱导的内皮细胞凋亡中的作用。

方法

将20只雄性Wistar大鼠随机分为两组，即HPH组和对照组，每组10只。通过将大鼠置于等压舱[氧气含量 = （10 ± 0.5）%]中3周建立HPH模型。采用链霉亲和素过氧化物酶法（SP）观察肺组织中BMP-2的分布，通过图像分析测定肺小动脉的形态学变化及BMP-2的积分光密度（IA）。用流式细胞仪检测Noggin（一种BMP阻断剂）对缺氧培养的人脐静脉内皮细胞（HUVEC）凋亡的影响。

结果

与对照组相比，低氧大鼠肺动脉高压明显：平均肺动脉压（mPAP）为16.3 ± 0.5 mmHg（1 mmHg = 0.133 kPa），而（29.5 ± 0.9）mmHg，P < 0.01。低氧大鼠肺小动脉壁明显增厚；壁厚百分比（WT%）为（16 ± 5）%，而（27 ± 7）%，壁面积百分比（WA%）为（54 ± 11）%，而（80 ± 8）%，两者P < 0.01。BMP-2主要分布在肺小动脉壁。BMP-2的IA显著增加（6124 ± 1199对13463 ± 5755，P < 0.01），且分别与WT%和WA%呈正线性关系（WT%：r = 0.744，P < 0.01；WA%：r = 0.693，P < 0.01）。缺氧诱导HUVEC凋亡；暴露于缺氧24小时和48小时后，凋亡率分别从6%增加到14%和25%。Noggin将缺氧诱导的HUVEC凋亡率降低至11.91%（24小时）和15.01%（48小时）。