Implication for transglutaminase 2-mediated activation of β-catenin signaling in neointimal vascular smooth muscle cells in chronic cardiac allograft rejection

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains the main cause of long-term transplant rejection. CAV is characterized by hyperproliferation of vascular smooth muscle cells (VSMCs). Canonical beta-catenin signaling is a critical regulator of VSMC proliferation in development; however, the role of this pathway and its regulation in CAV progression are obscure. We investigated the activity of beta-catenin signaling and the role for a putative activating ligand, transglutaminase 2 (TG2), in chronic cardiac rejection. METHODS: Hearts from Bm12 mice were transplanted into C57BL/6 mice (class II mismatch), and allografts were harvested 8 weeks after transplantation. Accumulation and sub-cellular distribution of beta-catenin protein and expression of several components of p-catenin signaling were analyzed as hallmarks of pathway activation. In vitro, platelet-derived growth factor treatment was used to mimic the inflammatory milieu in VSMC and organotypic heart slice cultures. RESULTS: Activation of P-catenin in allografts compared with isografts or naive hearts was evidenced by the augmented expression of E-catenin target genes, as well as the accumulation and nuclear localization of the beta-catenin protein in VSMCs of the occluded allograft vessels. Expression of TG2, an activator of beta-catenin signaling in VSMCs, was dramatically increased in allografts. Further, our ex vivo data demonstrate that TG2 is required for VSMC proliferation and for beta-catenin activation by platelet-derived growth factor in cardiac tissue. CONCLUSIONS: beta-Catenin signaling is activated in occluded vessels in murine cardiac allografts. TG2 is implicated as an endogenous activator of this signaling pathway and may therefore have a role in the pathogenesis of CAV during chronic allograft rejection. J Heart Lung Transplant 2012;31:1009-17 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved.