Pygo1 regulates pathological cardiac hypertrophy via a β-catenin-dependent mechanism

Abstract

Wnt/β-catenin signalling plays a key role in pathological cardiac remodelling in adults. The identification of a tissue-specific Wnt/β-catenin interaction factor may realise a tissue-specific clinical targeting strategy. Drosophila Pygo codes for 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, Pygo1is enriched in cardiac tissue. However, the role of Pygo1 in mammalian cardiac disease remains unelucidated. Here, 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 complex was abundant in Pygo1-overexpressingtransgenic(Pygo1-TG) cardiac tissue,and the downstream genes of Wnt signaling, i.e., 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 remodelling 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 a tissue-specific clinical treatment targeting this pathway.

WNT/β‐catenin pathway is a key regulator of cardiac function and energetic metabolism

“…The in vivo silencing of Pygo1 also attenuates the development of isoproterenol-induced heart hypertrophy. 187 More evidence of the hypertrophic action of βcatenin comes from Dvl-1-overexpressing and αEcatenin knockout mice. In both cases, levels of active βcatenin increased because of liberation from the destruction complex and adherens junction, respectively.…”

“…This observed phenotype was rescued by pharmacological inhibition of the transcriptional function of β‐catenin. The in vivo silencing of Pygo1 also attenuates the development of isoproterenol‐induced heart hypertrophy 187 . More evidence of the hypertrophic action of β‐catenin comes from Dvl‐1‐overexpressing and αE‐catenin knockout mice.…”

Novel biphasic mechanism of the canonical Wnt signalling component PYGO2 promotes cardiomyocyte differentiation from hUC-MSCs

“…Inhibitors of canonical Wnt signalling, such as Frizzled and Dkk-1, induce cardiac gene expression in the posterior lateral plate mesoderm (Marvin et al 2001 ). Our previous study showed that PYGO, which does not regulate the formation of adult cardiac valves, functions through canonical Wnt signalling (Lin et al 2021 ; Tang et al 2013 ). While investigating hUC-MSCs differentiation and cardiomyocyte-like cell formation, we adopted a different approach not used in other studies (Joshi et al 2018 ; Pham et al 2016 ; Ruan et al 2016 ).…”

Interactions between the ERK1/2 signaling pathway and PCAF play a key role in PE‑induced cardiomyocyte hypertrophy

“…Existing reports indicate that histone modification and DNA methylation are involved in the occurrence and development of myocardial hypertrophy ( 37 , 38 ). The occurrence and development of cardiac hypertrophy is also accompanied by the abnormal activation of a large number of important signaling pathways ( 5 , 39 , 40 ). Consequently, there is an increased level of interest in how key signaling pathways participate in the epigenetic regulation of cardiac hypertrophy ( 41 , 42 ).…”