<i>Pygo1</i> regulates pathological cardiac hypertrophy via a β-catenin-dependent mechanism

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. <i>Drosophila Pygo</i> encodes the core interaction factor of Wnt/β-catenin. Two <i>Pygo</i> homologs (<i><i><i>Pygo1</i></i></i> and <i>Pygo2</i>) have been identified in mammals. Different from the ubiquitous expression profile of <i>Pygo2</i>, <i><i><i>Pygo1</i></i></i> is enriched in cardiac tissue. However, the role of <i><i><i>Pygo1</i></i></i> in mammalian cardiac disease is yet to be elucidated. In this study, we found that <i><i><i>Pygo1</i></i></i> was upregulated in human cardiac tissues with pathological hypertrophy. Cardiac-specific overexpression of <i><i><i>Pygo1</i></i></i> 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 <i><i><i>Pygo1</i></i></i>-overexpressing transgenic (<i><i><i>Pygo1</i></i></i>-TG) cardiac tissue, and the downstream genes of Wnt signaling, that is, <i><i>Axin2</i></i>, <i>Ephb3</i>, 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 <i><i><i>Pygo1</i></i></i>-TG mice. Furthermore, in vivo downregulated <i>pygo1</i> during cardiac hypertrophic condition antagonized agonist-induced cardiac hypertrophy. Therefore, our study is the first to present in vivo evidence demonstrating that <i><i><i>Pygo1</i></i></i> 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.<b>NEW & NOTEWORTHY</b> In this study, we found that <i>Pygo1</i> is associated with human pathological hypertrophy. Cardiac-specific overexpression of <i>Pygo1</i> in mice spontaneously led to cardiac hypertrophy. Meanwhile, cardiac function was improved when expression of <i>Pygo1</i> was interfered in hypertrophy-model mice. Our study is the first to present in vivo evidence demonstrating that <i>Pygo1</i> 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.