Genetic inactivation of β-catenin is salubrious, whereas its activation is deleterious in desmoplakin cardiomyopathy

桥粒蛋白 MYH6 普氏球蛋白 连环素 癌症研究 心肌病 物候学 Wnt信号通路 内科学 生物 细胞生物学 医学 信号转导 心力衰竭 遗传学 基因 表型 MYH7 肌球蛋白轻链激酶 磷酸化
作者
Melis Olcum,Siyang Fan,Leila Rouhi,Sirisha Cheedipudi,Benjamin Cathcart,Hyun-Hwan Jeong,Zhongming Zhao,Priyatansh Gurha,Ali J. Marian
出处
期刊:Cardiovascular Research [Oxford University Press]
卷期号:119 (17): 2712-2728 被引量:1
标识
DOI:10.1093/cvr/cvad137
摘要

Abstract Aims Mutations in the DSP gene encoding desmoplakin, a constituent of the desmosomes at the intercalated discs (IDs), cause a phenotype that spans arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy. It is typically characterized by biventricular enlargement and dysfunction, myocardial fibrosis, cell death, and arrhythmias. The canonical wingless-related integration (cWNT)/β-catenin pathway is implicated in the pathogenesis of ACM. The β-catenin is an indispensable co-transcriptional regulator of the cWNT pathway and a member of the IDs. We genetically inactivated or activated β-catenin to determine its role in the pathogenesis of desmoplakin cardiomyopathy. Methods and results The Dsp gene was conditionally deleted in the 2-week-old post-natal cardiac myocytes using tamoxifen-inducible MerCreMer mice (Myh6-McmTam:DspF/F). The cWNT/β-catenin pathway was markedly dysregulated in the Myh6-McmTam:DspF/F cardiac myocytes, as indicated by a concomitant increase in the expression of cWNT/β-catenin target genes, isoforms of its key co-effectors, and the inhibitors of the pathway. The β-catenin was inactivated or activated upon inducible deletion of its transcriptional or degron domain, respectively, in the Myh6-McmTam:DspF/F cardiac myocytes. Genetic inactivation of β-catenin in the Myh6-McmTam:DspF/F mice prolonged survival, improved cardiac function, reduced cardiac arrhythmias, and attenuated myocardial fibrosis, and cell death caused by apoptosis, necroptosis, and pyroptosis, i.e. PANoptosis. In contrast, activation of β-catenin had the opposite effects. The deleterious and the salubrious effects were independent of changes in the expression levels of the cWNT target genes and were associated with changes in several molecular and biological pathways, including cell death programmes. Conclusion The cWNT/β-catenin was markedly dysregulated in the cardiac myocytes in a mouse model of desmoplakin cardiomyopathy. Inactivation of β-catenin attenuated, whereas its activation aggravated the phenotype, through multiple molecular pathways, independent of the cWNT transcriptional activity. Thus, suppression but not activation of β-catenin might be beneficial in desmoplakin cardiomyopathy.
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