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

Kelly E. Beazley, Tianshu Zhang, Florence Lima, Tatyana Pozharskaya, Corinne Niger, Erdyni Tzitzikov, Agnes M. Azimzadeh, Maria Nurminskaya

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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 languageEnglish
Pages (from-to)1009-1017
Number of pages9
JournalJournal of Heart and Lung Transplantation
Issue number9
StatePublished - 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.


  • 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


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