Publications by authors named "Ashley J Sizer"

3 Publications

  • Page 1 of 1

TET2 Protects Against VSMC Apoptosis and Intimal Thickening in Transplant Vasculopathy.

Circulation 2021 Jun 11. Epub 2021 Jun 11.

Department of Medicine (Cardiovascular Medicine), Yale University School of Medicine, New Haven, CT.

Coronary allograft vasculopathy (CAV) is a devastating sequelae of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. TET methylcytosine dioxygenase 2 (TET2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown. We assessed TET2 expression and activity in human CAV and renal transplant samples. We also employed the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild type and inducible smooth muscle-specific knockout mice; and studies in murine and human VSMCs using knockdown, overexpression, and transcriptomic approaches to assess the role of TET2 in VSMC responses to IFNу, a cytokine elaborated by T cells that drives CAV progression. In the present study, we found that TET2 expression and activity is negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNу was sufficient to repress TET2 and induce an activated VSMC phenotype . TET2 depletion mimicked the effects of IFNу, and TET2 overexpression rescued IFNу-induced dedifferentiation. VSMC-specific TET2 depletion in aortic grafts, and in the femoral wire restenosis model, resulted in increased VSMC apoptosis and medial thinning. In GA, this apoptosis was tightly correlated with proliferation. , TET2 deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. Notably, enhancing TET2 enzymatic activity with high-dose ascorbic acid rescued the effect of GA-induced VSMC apoptosis and intimal thickening in a TET2-dependent manner. TET2 is repressed in CAV and GA, likely mediated by IFNу. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNу stimulation. Promoting TET2 activity with systemic ascorbic acid reduces VSMC apoptosis and intimal thickening. These data suggest that promoting TET2 activity in CAV may be an effective strategy for limiting CAV progression.
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June 2021

LMO7 Is a Negative Feedback Regulator of Transforming Growth Factor β Signaling and Fibrosis.

Circulation 2019 01;139(5):679-693

Departments of Medicine (Cardiovascular Medicine) (Y.X., A.C.O., Y.J., K.A.M., J.H.), Yale University, New Haven, CT.

Background: Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown.

Methods: We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle-specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis.

Results: We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1-dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy.

Conclusions: LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.
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January 2019

Respecting boundaries: CTCF, chromatin structural organization, and heart failure.

J Thorac Dis 2017 Dec;9(12):4889-4892

Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT, USA.

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December 2017