[1]周洋,刘凌曦,唐仕海,等.β链蛋白在慢性缺氧诱导小鼠心肌肥厚中的作用[J].第三军医大学学报,2017,39(16):1637-1642.
 ZHOU Yang,LIU Lingxi,TANG Shihai,et al.Role of β-catenin in hypoxia-induced right ventricular hypertrophy[J].J Third Mil Med Univ,2017,39(16):1637-1642.
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β链蛋白在慢性缺氧诱导小鼠心肌肥厚中的作用(/HTML )
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《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

卷:
39卷
期数:
2017年第16期
页码:
1637-1642
栏目:
基础医学
出版日期:
2017-08-30

文章信息/Info

Title:
Role of β-catenin in hypoxia-induced right ventricular hypertrophy
作者:
周洋刘凌曦唐仕海彭华利
乐山市人民医院胸心外科;第三军医大学新桥医院心血管外科
Author(s):
ZHOU Yang LIU Lingxi TANG Shihai PENG Huali

Department of Cardiothoracic Surgery, People’s Hospital of Leshan, Leshan, Sichuan Province, 614000; Department of Cardiovascular Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China

关键词:
&beta链蛋白紫绀型先天性心脏病心肌肥厚缺氧
Keywords:
&beta-catenin cyanotic congenital heart disease myocardial hypertrophy hypoxia
分类号:
R363.21;R364.4;R542.2
文献标志码:
A
摘要:

目的     探讨β链蛋白(βcatenin)在缺氧诱导的心肌肥厚中的作用,并寻找可能的干预靶点。方法     ①收集第三军医大学新桥医院心外科2015年10月到2016年8月收治的21例先心病患儿的右室流出道临床心肌标本,常氧组(室间隔缺损伴右室流出道狭窄,血氧饱和度≥95%)10例和缺氧组(法洛氏四联征,血氧饱和度<85%)11例,术中取右室流出道心肌组织作为标本,用免疫荧光检测心肌细胞面积,Western blot检测心肌胞质、胞核βcatenin含量。②选取25只成年C57小鼠,按照随机数字表法分为常氧4周组、缺氧4周组、缺氧4周+激动剂(CHIR-9901)组、缺氧4周+抑制剂(IWR1)组和缺氧+生理盐水组(n=5)。常氧4周组和缺氧4周组于缺氧第4周取出心脏。小鼠缺氧模型采用10%氧浓度连续缺氧4周。通过免疫荧光标记细胞膜并测量心肌细胞面积,Western blot检测心肌中胞质和胞核的β0catenin及Cyclin D1的蛋白含量。③缺氧4周+激动剂组、缺氧4周+抑制剂组和缺氧4周+生理盐水组均在缺氧3周后,在缺氧舱内腹腔注射给药,第4周取得心脏。通过观察心室质量和心肌细胞面积比较心肌肥厚程度,小动物心导管检测心脏功能。结果    ①临床标本中,相对于非紫绀组心肌,紫绀组的心肌面积明显增加(P<0.05),且伴随着胞核、胞质中β-catenin的蛋白表达减少。②小鼠慢性缺氧模型中,缺氧4周组明显出现心肌细胞面积增加(P<0.05),右心室与体质量的比值增加(P<0.05),右心射血分数降低(P<0.05),并伴随着胞核、胞质中β-catenin的蛋白表达减少。③与缺氧4周+生理盐水组比较,缺氧4周+激动剂组的心肌细胞面积减少(P<0.05),右心室与体质量的比值减少(P<0.05),右心射血分数增加(P<0.05),胞核β-catenin水平和下游靶基因Cyclin D1表达水平明显增加,而缺氧4周+抑制剂组无明显变化(P>0.05)。结论     在慢性缺氧引起右心室肥厚过程中,β-catenin激活进入胞核,能减轻心肌肥厚,并改善心脏功能。

Abstract:

Objective     To determine the role of β-catenin in hypoxia-induced right ventricular hypertrophy, and investigate the potential medical target. Methods     Myocardial tissue specimens were collected from the right ventricular outflow tract of 21 children with congenital heart disease during operation, who were hospitalized in the Department of Cardiovascular Surgery of Xinqiao Hospital from October 2015 to August 2016 (including 11 cases of cyanotic type, with postoperative diagnosis as Tetralogy of Fallot, and  blood oxygen saturation of ≤85%, and 10 cases of acyanotic type, with postoperative diagnosis as interventricular septal defect and right ventricular outflow tract stenosis, and blood oxygen saturation of ≥95%). The area of cardiomyocytes was measured by immunofluorescence assay, and the protein level of βcatenin in the cytoplasm and nucleus were determined by Western blotting. Twentyfive C57BL/6J mice were randomly divided into 4-week normoxia group, 4-week hypoxia group, and 4-week hypoxia+activator (CHIR-9901), +inhibitor (IWR-1) and +normal saline groups (n=5). After 4 weeks of hypoxia (10% O2) or normoxia, the rats were executed and the hearts were immediately taken out to isolate the right ventricle. The area of cardiomyocyte was detected by immunofluorescence assay. Western blotting was adopted to detect the protein level of βcatenin and Cyclin D1 in the cytoplasm and nucleus. In the 4-week hypoxia+activator, +inhibitor and +normal saline groups, the related agents were intraperitoneally injected in the hypoxic chamber at the beginning of the 4th week of hypoxia. After the heart was taken after the hypoxia, the weight of right ventricle and the area of cardiomyocytes were used to evaluate the degree of myocardial hypertrophy, and the cardiac function was measured by cardiac catheterization. Results     The cyanotic group had significantly larger area of cardiomyocytes (P<0.05), and lower protein level of β-catenin in the cytoplasm and nucleus as compared with the acyanosis group. The mouse model of chronic hypoxia showed larger area of cardiomyocytes (P<0.05), higher ratio of right ventricle weight to body weight  (P<0.05), lower right ventricular ejection fraction (P<0.05), and decreased expression level of β-catenin in the cytoplasm and nucleus.  Compared with the 4-week hypoxia+normal saline group, the 4-week hypoxia+activator group displayed smaller area of cardiomyocytes (P<0.05), lower ratio of right ventricle to body weight (P<0.05), increased right ventricular ejection fraction (P<0.05), and increased level of βcatenin in the nucleus and its downstream Cyclin D1. However, no such changes were observed in the 4-week hypoxia+inhibitor group (P>0.05). Conclusion     During the process of chronic hypoxiainduced right ventricular hypertrophy, β-catenin enters the nuclei after activation, and then alleviates myocardial hypertrophy and improves cardiac function.

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更新日期/Last Update: 2017-08-23