FZD2 inhibits YAP and prevents cell cycle reentry in adult murine cardiomyocytes

Abstract

ABSTRACTRationaleFully differentiated cardiomyocytes (CMs) are post-mitotic and cannot repopulate damaged tissue after myocardial infarction (MI). Understanding the mechanisms preventing CM proliferation or promoting their survival after injury may lead to treatment strategies for MI. While the effects of canonical WNT/β-catenin signaling in adult CMs have been examined, roles for non-canonical WNT signaling in cardiac homeostasis and repair remain unexplored.ObjectiveTo determine the function of the non-canonical WNT receptor frizzled 2 (FZD2) in adult cardiac homeostasis and injury.Methods and ResultsFZD2 was deleted from the CMs of adult mice to investigate its role in myocardial homeostasis.Fzd2conditional knockout (CKO) mice had cardiomegaly but not hypertrophy. FZD2-deficient CMs expressed proliferation and cytokinesis markers, suggesting that they have increased proliferation potential. FZD2-deletion caused the accumulation of β-catenin. However, β-catenin localized to the membranes of FZD2-deficient CMs and did not activate target gene expression. Instead, the YES-associated protein (YAP) regulated genesv-myc avian myelocytomatosis viral oncogene 1 (Mycl), andB cell leukemia/lymphoma 2 (Bcl2l1)were upregulated inFzd2CKO CMs relative to controls. Knockdown of FZD2 increased YAP activity in neonatal ventricular CMs (NVCMs), while overexpressing FZD2 inhibited YAP. Neither β-catenin knockdown nor mutating the large tumor suppressor 1 and 2 (LATS1/2) target site on YAP blocked the effects of FZD2 on YAP in NVCMs, suggesting that FZD2 utilizes different effectors than canonical WNT and Hippo signaling.Fzd2CKO and control mice were subjected to MI to determine if FZD2-deletion affects cardiac repair. While ischemia and necrosis were similar 24 hours post MI,Fzd2CKO mice had better cardiac function and less scarring than controls.ConclusionsFZD2 reduces YAP activity and prevents adult murine CMs from reentering the cell cycle. FZD2-deletion improves heart function and reduces scarring in mice after MI, implicating FZD2 as a target for pharmacological intervention.