Abstract
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 β-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 β-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 β-catenin protein and expression of several components of β-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 β-catenin in allografts compared with isografts or naïve hearts was evidenced by the augmented expression of β-catenin target genes, as well as the accumulation and nuclear localization of the β-catenin protein in VSMCs of the occluded allograft vessels. Expression of TG2, an activator of β-catenin signaling in VSMCs, was dramatically increased in allografts. Further, our ex vivo data demonstrate that TG2 is required for VSMC proliferation and for β-catenin activation by platelet-derived growth factor in cardiac tissue. Conclusions: β-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.
Original language | English |
---|---|
Pages (from-to) | 1009-1017 |
Number of pages | 9 |
Journal | Journal of Heart and Lung Transplantation |
Volume | 31 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2012 |
Bibliographical note
Funding Information:This work was supported by grants from the National Institutes of Health : R01HL093305 awarded to M.N., T32AR007592 fellowship to K.B., 5UO1-AI066719 awarded to R.N. P., and a University of Maryland Greenebaum Cancer Center Award to A.A.
Keywords
- cardiac allograft vasculopathy
- platelet derived growth factor
- transglutaminase 2
- vascular smooth muscle cells
- β-catenin signaling
ASJC Scopus subject areas
- Surgery
- Pulmonary and Respiratory Medicine
- Cardiology and Cardiovascular Medicine
- Transplantation