Abstract 387: Apolipoprotein E Receptor-2 Restricts Cardiomyocyte Proliferation and Controls Heart Size

Abstract

Introduction: Apolipoprotein E receptor 2 (ApoER2) is highly expressed in brain and testes, but also in macrophages, endothelial and vascular smooth muscle cells, as well as heart. Importantly, genome-wide association studies have linked polymorphisms in the LRP8 gene to familial and premature coronary artery disease (CAD) and myocardial infarction (MI). However, the mechanisms by which ApoER2, the protein encoded by the LRP8 gene, affect CAD and MI are incompletely understood. Hypothesis: The goal of the current study was to examine the function of ApoER2 in the heart. Methods and Results: Morphological analysis revealed an increase in heart size and cross-sectional area with elevated cardiomyocyte proliferation in mice deficient for ApoER2 compared to wild-type control mice. Echocardiography showed a significant increase in left ventricular diameter in ApoER2 KO mice, while no significant differences in fractional shortening and ejection fraction were observed. Loss of ApoER2 attenuated expression of Disabled-2 (Dab2) and Axin2, thereby preventing formation of the destruction complex, resulting in increased levels of β-catenin. Consistent with previous studies that demonstrated that stabilized β-catenin alters expression of the T-box protein Tbx20, ApoER2 deficiency was associated with increased Tbx20 expression, a transcription factor necessary and sufficient to promote cardiomyocyte proliferation. Conclusions: Together, these data indicate that ApoER2 promotes β-catenin degradation and modulates Tbx20 expression to restrain cardiomyocyte proliferation and heart size, providing a mechanism by which ApoER2 dysfunction may contribute to premature CAD and MI.