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

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