1. Pygo1 regulates pathological cardiac hypertrophy via a β-catenin-dependent mechanism.
- Author
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Lin L, Xu W, Li Y, Zhu P, Yuan W, Liu M, Shi Y, Chen Y, Liang J, Chen J, Yang B, Cai W, Wen Y, Zhu X, Peng X, Zhou Z, Mo X, Wan Y, Yuan H, Li F, Ye X, Jiang Z, Wang Y, Zhuang J, Fan X, and Wu X
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Axin Protein genetics, Axin Protein metabolism, Disease Models, Animal, Heart Failure chemically induced, Heart Failure pathology, Heart Failure prevention & control, Hypertrophy, Left Ventricular chemically induced, Hypertrophy, Left Ventricular drug therapy, Hypertrophy, Left Ventricular pathology, Isoproterenol, Male, Mice, Transgenic, Myocardium pathology, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, Rats, Receptor, EphB3 genetics, Receptor, EphB3 metabolism, Thiazolidines pharmacology, Transcription Factor 4 genetics, Transcription Factor 4 metabolism, beta Catenin antagonists & inhibitors, Adaptor Proteins, Signal Transducing metabolism, Heart Failure metabolism, Hypertrophy, Left Ventricular metabolism, Myocardium metabolism, Ventricular Function, Left drug effects, Ventricular Remodeling drug effects, Wnt Signaling Pathway drug effects, beta Catenin metabolism
- Abstract
Wnt/β-catenin signaling plays a key role in pathological cardiac remodeling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may provide a tissue-specific clinical targeting strategy. Drosophila Pygo encodes the core interaction factor of Wnt/β-catenin. Two Pygo homologs ( Pygo1 and Pygo2 ) have been identified in mammals. Different from the ubiquitous expression profile of Pygo2 , Pygo1 is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease is yet to be elucidated. In this study, we found that Pygo1 was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy accompanied by declined cardiac function, increased heart weight/body weight and heart weight/tibial length ratios, and increased cell size. The canonical β-catenin/T-cell transcription factor 4 (TCF4) complex was abundant in Pygo1 -overexpressing transgenic ( Pygo1 -TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, Axin2 , Ephb3 , and c-Myc, were upregulated. A tail vein injection of β-catenin inhibitor effectively rescued the phenotype of cardiac failure and pathological myocardial remodeling in Pygo1 -TG mice. Furthermore, in vivo downregulated pygo1 during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for tissue-specific clinical treatment via targeting this pathway. NEW & NOTEWORTHY In this study, we found that Pygo1 is associated with human pathological hypertrophy. Cardiac-specific overexpression of Pygo1 in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of Pygo1 was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that Pygo1 regulates pathological cardiac hypertrophy in a canonical Wnt/β-catenin-dependent manner, which may provide new clues for a tissue-specific clinical treatment targeting this pathway.
- Published
- 2021
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