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

ABSTRACT: 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 ?-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 ?-catenin signaling and the role for a putative activating ligand, transglutaminase 2 (TG2), in chronic cardiac rejection.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 ?-catenin protein and expression of several components of ?-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.Activation of ?-catenin in allografts compared with isografts or naïve hearts was evidenced by the augmented expression of ?-catenin target genes, as well as the accumulation and nuclear localization of the ?-catenin protein in VSMCs of the occluded allograft vessels. Expression of TG2, an activator of ?-catenin signaling in VSMCs, was dramatically increased in allografts. Further, our ex vivo data demonstrate that TG2 is required for VSMC proliferation and for ?-catenin activation by platelet-derived growth factor in cardiac tissue.?-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.

SUBMITTER: Beazley KE

PROVIDER: S-EPMC3509739 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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

Beazley Kelly E KE Zhang Tianshu T Lima Florence F Pozharskaya Tatyana T Niger Corinne C Tzitzikov Erdyni E Azimzadeh Agnes M AM Nurminskaya Maria M

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20120612 9

<h4>Background</h4>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), ...[more]

PMID: 22694852

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Project description:Objective- Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results- We found by immunofluorescent staining that CD36 was highly expressed in human vessels with obstructive diseases. Using guidewire-induced carotid artery injury and shear stress-induced intima thickening models, we compared neointimal hyperplasia in Apoe-/-, Cd36-/- /Apoe-/-, and CD36 specifically deleted in VSMC (VSMC cd36-/-) mice. CD36 deficiency, either global or VSMC-specific, dramatically reduced injury-induced neointimal thickening. Correspondingly, carotid artery blood flow was significantly increased in Cd36-/- /Apoe-/- compared with Apoe-/- mice. In cultured VSMCs from thoracic aorta of wild-type and Cd36-/- mice, we found that loss of CD36 significantly decreased serum-stimulated proliferation and increased cell populations in S phase, suggesting that CD36 is necessary for VSMC S/G2-M-phase transition. Treatment of VSMCs with a TSR (thrombospondin type 1 repeat) peptide significantly increased wild-type, but not Cd36-/- VSMC proliferation. TSR or serum treatment significantly increased cyclin A expression in wild-type, but not in Cd36-/- VSMCs. STAT3 (signal transducer and activator of transcription), which reportedly enhances both VSMC differentiation and maturation, was higher in Cd36-/- VSMCs. CD36 deficiency significantly decreased expression of Col1A1 (type 1 collagen A1 chain) and TGF-?1 (transforming growth factor beta 1), and increased expression of contractile proteins, including calponin 1 and smooth muscle ? actin, and dramatically increased cell contraction. Conclusions- CD36 promotes VSMC proliferation via upregulation of cyclin A expression that contributes to the development of neointimal hyperplasia, collagen deposition, and obstructive vascular diseases.

Dataset Information

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

Publications

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

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