YAP1 介导的 ACE-ACE2 活性失调会在诱导高血糖应激时加重心脏纤维化。

IF 2.8 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et biophysica acta. General subjects Pub Date : 2024-06-30 DOI:10.1016/j.bbagen.2024.130666
Arunima Mondal , Shreya Das , Madhuchhanda Das , Santanu Chakraborty , Arunima Sengupta
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引用次数: 0

摘要

背景:糖尿病压力作用于心脏组织,诱发心脏肥大和纤维化。据报道,糖尿病诱导的活化肾素血管紧张素系统(RAS)在介导心脏肥大和纤维化方面起着关键作用。血管紧张素转换酶(ACE)产生血管紧张素-II,促进心肌细胞肥大和纤维化损伤。据报道,最近发现的与血管紧张素转换酶结构同源的分子 ACE2 有助于减轻 RAS 驱动的病变的影响:方法:使用体内糖尿病小鼠模型和共标记免疫染色法分析小鼠心脏组织的纤维化重塑和相关靶信号分子的参与。在体外分析中,对不同组的 RNA 和蛋白质表达进行了 qPCR 和 Western 印迹实验:结果:在糖尿病小鼠心脏组织以及经高糖处理的成纤维细胞和心肌细胞中观察到纤维化标志物上调。高血糖诱导的 YAP1 过表达导致β-catenin(CTNNB1)和 ACE 的表达增加,而 ACE2 的表达下调。ACE/ACE2的不同表达促进了高血糖心肌细胞和成纤维细胞中的TGFB1-SMAD2/3通路,导致心脏纤维化重塑增加:在接下来的研究中,我们报道了 YAP1 通过诱导 ACE 和抑制 ACE2 的活性来调节 RAS 信号通路,从而在高血糖条件下促进心肌细胞肥大和纤维化。此外,我们还发现,高血糖诱导的 YAP1 对 ACE-ACE2 活性的失调会通过 β-catenin/TGFB1 依赖性途径促进心脏纤维化。
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YAP1-mediated dysregulation of ACE-ACE2 activity augments cardiac fibrosis upon induction of hyperglycemic stress

Background

Diabetic stress acts on the cardiac tissue to induce cardiac hypertrophy and fibrosis. Diabetes induced activated renin angiotensin system (RAS) has been reported to play a critical role in mediating cardiac hypertrophy and fibrosis. Angiotensin converting enzyme (ACE) in producing Angiotensin-II, promotes cardiomyocyte hypertrophy and fibrotic damage. ACE2, a recently discovered molecule structurally homologous to ACE, has been reported to be beneficial in reducing the effect of RAS driven pathologies.

Methods

In vivo diabetic mouse model was used and co-labelling immunostaining assay have been performed to analyse the fibrotic remodeling and involvement of associated target signaling molecules in mouse heart tissue. For in vitro analyses, qPCR and western blot experiments were performed in different groups for RNA and protein expression analyses.

Results

Fibrosis markers were observed to be upregulated in the diabetic mouse heart tissue as well as in high glucose treated fibroblast and cardiomyocyte cells. Hyperglycemia induced overexpression of YAP1 leads to increased expression of β-catenin (CTNNB1) and ACE with downregulated ACE2 expression. The differential expression of ACE/ACE2 promotes TGFB1-SMAD2/3 pathway in the hyperglycemic cardiomyocyte and fibroblast resulting in increased cardiac fibrotic remodeling.

Conclusion

In the following study, we have reported YAP1 modulates the RAS signaling pathway by inducing ACE and inhibiting ACE2 activity to augment cardiomyocyte hypertrophy and fibrosis in hyperglycemic condition. Furthermore, we have shown that hyperglycemia induced dysregulation of ACE-ACE2 activity by YAP1 promotes cardiac fibrosis through β-catenin/TGFB1 dependent pathway.

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来源期刊
Biochimica et biophysica acta. General subjects
Biochimica et biophysica acta. General subjects 生物-生化与分子生物学
CiteScore
6.40
自引率
0.00%
发文量
139
审稿时长
30 days
期刊介绍: BBA General Subjects accepts for submission either original, hypothesis-driven studies or reviews covering subjects in biochemistry and biophysics that are considered to have general interest for a wide audience. Manuscripts with interdisciplinary approaches are especially encouraged.
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