Hyperthyroidism Induces Ventricular Remodeling via Activating β-catenin/FoxO1 in Rat Cardiomyocytes

YUAN Xun; BAN Li; TIAN Songlin; ZHU Qiulian; ZHANG Guiping; QIN Yuan; PAN Li; HOU Ning

doi:10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240515.003

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Hyperthyroidism Induces Ventricular Remodeling via Activating β-catenin/FoxO1 in Rat Cardiomyocytes

Preclinic Research | 更新时间：2024-06-05

- Hyperthyroidism Induces Ventricular Remodeling via Activating β-catenin/FoxO1 in Rat Cardiomyocytes
- Journal of Sun Yat-sen University(Medical Sciences) Vol. 45, Issue 3, Pages: 393-411(2024)
- 作者机构：
  
  1.广州医科大学药学院药理学教研室 // 广州医科大学分子靶标与临床药理学重点实验室,广东广州 511436
  2.广州医科大学附属第五医院,广东广州 510799
  3.广州卫生职业技术学院生理教研室, 广东广州 510450
- 作者简介：
  
  PAN Li； E-mail： panlide292@163.com
  HOU Ning； E-mail： houning@gzhmu.edu.cn
- 基金信息：
- DOI：10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240515.003
  CLC： R966
- Published：20 May 2024，
  
  Received：22 March 2024，
  
  Accepted：03 May 2024
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袁勋,班莉,田松麟等.甲状腺功能亢进激活心肌细胞β-catenin/FoxO1诱导大鼠心室重构的作用[J].中山大学学报（医学科学版）,2024,45(03):393-411.

YUAN Xun,BAN Li,TIAN Songlin,et al.Hyperthyroidism Induces Ventricular Remodeling via Activating β-catenin/FoxO1 in Rat Cardiomyocytes[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(03):393-411.
袁勋,班莉,田松麟等.甲状腺功能亢进激活心肌细胞β-catenin/FoxO1诱导大鼠心室重构的作用[J].中山大学学报（医学科学版）,2024,45(03):393-411. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240515.003.

YUAN Xun,BAN Li,TIAN Songlin,et al.Hyperthyroidism Induces Ventricular Remodeling via Activating β-catenin/FoxO1 in Rat Cardiomyocytes[J].Journal of Sun Yat-sen University(Medical Sciences),2024,45(03):393-411. DOI： 10.13471/j.cnki.j.sun.yat-sen.univ（med.sci）.20240515.003.

摘要

目的

探究甲亢激活心肌细胞β-catenin/FoxO1诱导大鼠心室重构的作用和机制。

方法

通过甲状腺激素（T4 0.1 mg/kg/day；腹腔注射）连续给药30 d构建甲亢诱导心室重构大鼠体内模型。利用β-catenin抑制剂MSAB（14 mg/kg）同时给药30 d，通过Western-blot检测心肌肥厚主要标志物ANP以及β-catenin、FoxO1等蛋白的表达情况；免疫荧光检测β-catenin、FoxO1的核内外表达及分布情况。利用原代培养的乳鼠心肌细胞，使用甲状腺激素（T3 20 nmol/L）处理心肌细胞24 h构建体外甲亢诱导心肌细胞肥厚模型，利用β-cateninsiRNA（30 nmol/L）转染心肌细胞敲低β-catenin，Western-blot和免疫荧光检测抑制β-catenin对甲亢诱导乳鼠心肌细胞肥厚的影响。

结果

Wnt/β-catenin通路激活后β-catenin入核增多并于细胞核内的转录因子结合发挥转录调控作用。β-catenin在甲亢诱导的大鼠心室重构模型心肌细胞核内表达显著增加，而其经典下游转录因子TCF7l2表达无显著差异。我们的结果显示，MSAB抑制β-catenin明显改善甲亢诱导的大鼠心室重构。进一步研究表明甲亢诱导大鼠心肌肥厚过程中心肌细胞β-catenin/FoxO1表达明显增强，抑制心肌细胞β-catenin/FoxO1改善甲亢诱导大鼠心肌肥厚。

结论

甲亢性心肌肥厚心肌细胞β-catenin/FoxO1活化，抑制β-catenin/FoxO1改善甲状腺激素诱导的心肌细胞肥大。

Abstract

Objective

To explore how hyperthyroidism induces ventricular remodeling via activating β-catenin/FoxO1 in rat cardiomyocytes.

Methods

Hyperthyroidism-induced ventricular remodeling rat models were established by intraperitoneal injection of levothyroxine （T4） at 0.1 mg/kg for 30 days. β-catenin inhibitor MSAB （14 mg/kg） was administrated for 30 days. We used western blot to detect the expression of myocardial hypertrophy marker ANP， β-catenin and FoxO1； immunofluorescence to examine the expression and intracellular distribution of β-catenin and FoxO1. Hyperthyroidism-induced cardiomyocyte hypertrophy rat models were established by treatment of triiodothyronine （T3） into cultured primary neonatal rat cardiomyocytes for 24 hours. β-catenin siRNA （30 nmol/L） was used to down-regulate β-catenin expression in cardiomyocytes. Western blot and immunofluorescence were used to analyze the effects of β-catenin inhibition on the hyperthyroidism-induced cardiomyocyte hypertrophy.

Results

Following Wnt/β-catenin activation， β-catenin was found increased nuclear expression， to bind to the nuclear transcriptional factors and regulate the gene expression. β-catenin nuclear expression was significantly increased in the hyperthyroidism-induced ventricular remodeling rats， but no change was found in the expression of typical transcriptional factor TCF7l2. Our results revealed that inhibiting β-catenin by MSAB attenuated the hyperthyroidism-induced rat ventricular remodeling. Further analysis indicated that β-catenin/FoxO1 expression was significantly increased in hyperthyroidism-induced myocardial hypertrophy which could be attenuated by suppressing β-catenin/FoxO1 in cardiomyocytes.

Conclusions

β-catenin/FoxO1 is activated in hyperthyroidism-induced myocardial hypertrophy and β-catenin/FoxO1 inhibition attenuates hyperthyroidism-induced cardiomyocyte hypertrophy.

关键词

甲状腺功能亢进症心肌肥厚β-连环素叉头盒O1蛋白心肌细胞肥大MSAB甲状腺激素

Keywords

hyperthyroidismmyocardial hypertrophyβ-cateninFoxO1cardiomyocyte hypertrophyMSABthyroid hormone

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