|Table of Contents|

Role of β-catenin in hypoxia-induced right ventricular hypertrophy

(PDF)

《第三军医大学学报》[ISSN:1000-5404/CN:51-1095/R]

Issue:
2017年第16期
Page:
1637-1642
Research Field:
基础医学
Publishing date:

Info

Title:

Role of β-catenin in hypoxia-induced right ventricular hypertrophy

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

Keywords:

&beta-catenin cyanotic congenital heart disease myocardial hypertrophy hypoxia

PACS:
R363.21;R364.4;R542.2
DOI:
-
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.

References:

[1]HAGHIKIA A, STAPEL B, HOCH M, et al. STAT3 and cardiac remodeling[J]. Heart Fail Rev, 2011, 16(1): 35-47. DOI: 10.1007/s10741-010-9170-x.
[2]KEE H J, SOHN I S, NAM K I, et al. Inhibition of histone deacetylation blocks cardiac hypertrophy induced by angiotensin Ⅱ infusion and aortic banding[J]. Circulation, 2006, 113(1): 51-59. DOI: 10.1161/ CIRCULATIONAHA.105.559724.
[3]NAITO A T, SHIOJIMA I, AKAZAWA H, et al. Developmental stage-specific biphasic roles of Wnt/betacatenin signaling in cardiomyogenesis and hematopoiesis[J]. Proc Natl Acad Sci U S A, 2006, 103(52): 19812-19817. DOI: 10.1073/pnas.0605768103.
[4]LIN J C, KUO W W, BASKARAN R, et al. Enhancement of beta-catenin in cardiomyocytes suppresses survival protein expression but promotes apoptosis and fibrosis[J]. Cardiol J, 2017, 24(2): 195-205. DOI: 10.5603/CJ.a2016.0087.
[5]LI Q, HANNAH S S. Wnt/betacatenin signaling is downregulated but restored by nutrition interventions in the aged heart in mice[J]. Arch Gerontol Geriatr, 2012, 55(3): 749-754. DOI: 10.1016/ j.archger.2012.06.013.
[6]DEJANA E. The role of wnt signaling in physiological and pathological angiogenesis[J]. Circ Res, 2010, 107(8): 943-952. DOI: 10.1161/CIRCRESAHA.110.223750.
[7]CLEVERS H. Wnt/betacatenin signaling in development and disease[J]. Cell, 2006, 127(3): 469-480. DOI: 10.1016/j.cell.2012.05.012.
[8]蹇朝, 马瑞彦, 王咏, 等. 缺氧诱导因子-1α在紫绀型先心病患儿心肌中的表达[J]. 第三军医大学学报, 2009, 31(12): 1189-1192. DOI: 10.3321/j.issn: 1000-5404.2009.12.019.
JIAN Z, MA R Y, WANG Y, et al. Eepression of hypoxia inducible factor-1alpha in the myocardium of infants with cyanotic congenital heart defect[J]. J Third Mil Med Univ, 2009, 31(12): 1189-1192. DOI: 10.3321/j.issn: 1000-5404.2009.12.019.
[9]KOLAR F, OSTADAL B. Molecular mechanisms of cardiac protection by adaptation to chronic hypoxia[J]. Physiol Res, 2004, 53 Suppl 1: S3-S13.
[10]BREMBECK F H, ROSARIO M, BIRCHMEIER W. Balancing cell adhesion and Wnt signaling, the key role of beta-catenin[J]. Curr Opin Genet Dev, 2006, 16(1): 51-59. DOI: 10.1016/j.gde.2005.12.007.
[11]BAURAND A, ZELARAYAN L, BETNEY R, et al. Beta-catenin downregulation is required for adaptive cardiac remodeling[J]. Circ Res, 2007, 100(9): 1353-1362. DOI: 10.1161/01.RES.0000266605.63681.5a.
[12]CHEN X, SHEVTSOV S P, HSICH E, et al. The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stressinduced cardiac hypertrophy[J]. Mol Cell Biol, 2006, 26(12): 4462-4473. DOI: 10.1128/MCB.02157-05.
[13]JIN Y, WANG W, CHAI S, et al. Wnt5a attenuates hypoxiainduced pulmonary arteriolar remodeling and right ventricular hypertrophy in mice[J]. Exp Biol Med (Maywood), 2015, 240(12): 1742-1751. DOI: 10.1177/153537021 5584889.
[14]GARCIA-GRAS E, LOMBARDI R, GIOCONDO M J, et al. Suppression of canonical Wnt/betacatenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy[J]. J Clin Invest, 2006, 116(7): 2012-2021. DOI: 10.1172/JCI27751.

Memo

Memo:
-
Last Update: 2017-08-23