ArticleCirculation2021
TET2 Protects Against Vascular Smooth Muscle Cell Apoptosis and Intimal Thickening in Transplant Vasculopathy.
Article in Circulation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- Meta-Analysis of Single-Cell RNA-Seq Data Reveals the Mechanism of Formation and Heterogeneity of Tertiary Lymphoid Organ in Vascular Disease.Arteriosclerosis, thrombosis, and vascular biology · 2023Pooled it
- A potential role of the circ_UBR4/miR-10a-5p/KLF4 axis in regulating vascular smooth muscle cell phenotypic transformation : implications for cardiac allograft vasculopathy.Journal of cardiothoracic surgery · 2026Article
- PERK Is Dispensable for Smooth Muscle Cell Phenotype Switching in Atherosclerosis.Arteriosclerosis, thrombosis, and vascular biology · 2026Article
- The Complex Role of Methylation in Regulating Vascular Smooth Muscle Cell Phenotypic States in Vascular Remodeling and Atherosclerosis.Biomolecules · 2026Review
- Neointimal hyperplasia and vascular restenosis: from molecular mechanisms to therapeutic interventions.Molecular biomedicine · 2026Review
- ADAMTS7 promotes smooth muscle foam cell expansion in atherosclerosis.The Journal of clinical investigation · 2026Article
- VSMCs and the immune microenvironment: a multidimensional regulatory network driving vascular injury and repair.Frontiers in immunology · 2026Review
- Epigenetic regulation in transplant rejection and tolerance: mechanisms and therapeutic prospects.Frontiers in cardiovascular medicine · 2026Review
- Trained Immunity-Like Memory in Vascular Structural Cells: Metabolic-Epigenetic Reprogramming as a Driving Mechanism of Atherosclerosis and Residual Cardiovascular Risk.Journal of inflammation research · 2026Review
- Eugenol: A promising therapeutic terpenoid against ischemia-reperfusion injury.EXCLI journal · 2026Review
- METTL14 promotes intimal hyperplasia through m6A-mediated control of vascular smooth muscle dedifferentiation genes.JCI insight · 2025Article
- TET2 suppresses vascular calcification by forming an inhibitory complex with HDAC1/2 and SNIP1 independent of demethylation.The Journal of clinical investigation · 2025Article
- Localized COUP-TFII pDNA Delivery Modulates Stem/Progenitor Cell Differentiation to Enhance Endothelialization and Inhibit Calcification of Decellularized Allografts.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Ginger protects against vein graft remodeling by precisely modulating ferroptotic stress in vascular smooth muscle cell dedifferentiation.Journal of pharmaceutical analysis · 2025Article
- METTL16 Contributes to Coronary Heart Disease by Inducing TET2 m6A Modification.Journal of inflammation research · 2025Article
- Epigenetic modifications in vascular inflammation.Frontiers in immunology · 2025Review
- Unravelling the role of TET2 in venous thromboembolism: insights into mechanisms and therapeutic implications.Frontiers in cardiovascular medicine · 2025Review
- The functional significance of vascular DNA hypermethylation in atherosclerosis: a historical perspective.Frontiers in pharmacology · 2025Review
- CD34Theranostics · 2025Article
- TET2 germline variants promote kidney disease by impairing DNA repair and activating cytosolic nucleotide sensors.Nature communications · 2024Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundCoronary allograft vasculopathy (CAV) is a devastating sequela 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. TET2 (TET methylcytosine dioxygenase 2) is an important epigenetic regulator of VSMC phenotype, but the role of TET2 in the progression of CAV is unknown.
methodsWe assessed TET2 expression and activity in human CAV and renal transplant samples. We also used the sex-mismatched murine aortic graft model of graft arteriopathy (GA) in wild-type and inducible smooth muscle-specific
resultsIn the present study, we found that TET2 expression and activity are negatively regulated in human CAV and renal transplant samples and in the murine aortic graft model of GA. IFNγ was sufficient to repress TET2 and induce an activated VSMC phenotype in vitro. TET2 depletion mimicked the effects of IFNγ, and TET2 overexpression rescued IFNγ-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. In vitro, TET2-deficient VSMCs undergo apoptosis more readily in response to IFNγ and expressed a signature of increased susceptibility to extrinsic apoptotic signaling. 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.
conclusionsTET2 is repressed in CAV and GA, likely mediated by IFNγ. TET2 serves to protect VSMCs from apoptosis in the context of transplant vasculopathy or IFNγ stimulation. Promoting TET2 activity in vivo 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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Registered trials
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