Abstract 13121: Cardiac Specific Deletion of Adenomatous Polyposis Coli Promotes Cardiomyocyte Hyperplasia
The canonical Wnt/beta-catenin pathway has both positive and negative roles in early cardiogenesis. Germline mutation of adenomatous polyposis coli (APC), a negative regulator of beta-catenin, affects heart morphogenesis and results in embryonic lethality in zebrafish. The cell autonomous role of APC in cardiomyocyte (CM) remains poorly understood. Using alpha-myosin heavy chain promoter driven-Cre, we deleted APC specifically in the heart. Neonatal hearts deficient for APC increased in size, but demonstrated no congenital defects. On postnatal day (PD) 4, homozygous APC mice (KO, 41.17±11.63 mg, N=15) had almost double the heart weights of heterozygous (HT, 20.80±5.49 mg, N=24) and wild type (WT, 22.33±7.98 mg, N=57) littermates. More surprisingly, heart weights in KO animals (96.11±29.11 mg, N=18) were three times heavier than those of HT (34.58±6.57 mg, N=42) and WT (35.68±8.03 mg, N=103) mice on PD 8. The labeling indexes of Ki-67 and phosphohistone H3 at serine 10 were significantly increased in CM of KO. Without APC, beta-catenin was stabilized with decreased phosphorylations on serines 33/37/45 as well as threonine 41. This stabilization promoted nuclear translocation of beta-catenin and upregulated cell cycle regulators, especially cyclin D2 and c-myc. More importantly, chromatin immunoprecipitation and PCR revealed that beta-catenin was recruited to the promoter regions of cyclin D2 and c-myc. Our results indicate that cardiac specific APC deficiency does not impair cardiac patterning and chamber formation, but promotes CM proliferation. This challenges the notion that canonical Wnt/beta-catenin signaling has an inhibitory role in proliferating and differentiating CM after gastrulation.
- © 2011 by American Heart Association, Inc.