Abstract 632: Myeloid beta catenin Deficiency Exacerbates Atherosclerosis in Low-density Lipoprotein-receptor Deficient Mice

Abstract

Objective: The Wnt/β-catenin signaling is an ancient and evolutionarily conserved pathway that regulates essential aspects of cell differentiation, proliferation, migration and polarity, and canonical Wnt/β-catenin signaling has also been implicated in the pathogenesis of atherosclerosis. Macrophage is one of the major cell types involved in the initiation and progression of atherosclerosis, but the role of macrophage β-catenin in atherosclerosis remains elusive. This study aims to investigate the impact of β-catenin expression on macrophage functions and atherosclerosis development. Approaches and Results: To investigate the role of macrophage canonical Wnt/β-catenin signaling in atherogenesis, we generated low-density lipoprotein receptor-deficient (LDLR -/- ) mice with myeloid-specific β-catenin deficiency. As expected, deletion of β-catenin decreased macrophage adhesion and migration properties in vitro. However, deficiency of β-catenin significantly increased atherosclerosis in LDLR -/- mice without altering the plasma lipid levels. Mechanistic studies revealed that β-catenin can regulate activation of signal transducer and activator of transcription (STAT) pathway in macrophages, and ablation of β-catenin resulted in STAT3 downregulation and STAT1 activation, leading to elevated macrophage inflammatory responses and increased atherosclerosis. Conclusions: This study demonstrates a critical role of myeloid β-catenin expression in atherosclerosis by modulating macrophage inflammatory responses.