ArticleArteriosclerosis, thrombosis, and vascular biology2020
High Throughput Screen Identifies the DNMT1 (DNA Methyltransferase-1) Inhibitor, 5-Azacytidine, as a Potent Inducer of PTEN (Phosphatase and Tensin Homolog): Central Role for PTEN in 5-Azacytidine Protection Against Pathological Vascular Remodeling.
Article in Arteriosclerosis, thrombosis, and vascular biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 35 citations in OpenAlex.
- Therapeutic implications of epigenetic alterations in burns: a new frontier in burn medicine.Clinical science (London, England : 1979) · 2026Review
- The Complex Role of Methylation in Regulating Vascular Smooth Muscle Cell Phenotypic States in Vascular Remodeling and Atherosclerosis.Biomolecules · 2026Review
- Emerging Roles of Adenosine Metabolism in Astrocytes During Brain Injury.CNS neuroscience & therapeutics · 2026Review
- Chromatin Remodeling in VSMC Phenotype Switching During Vascular Remodeling: From Mechanism to Therapeutic Potential.Biomolecules · 2026Review
- Article
- Atherosclerosis in diabetes mellitus: novel mechanisms and mechanism-based therapeutic approaches.Nature reviews. Cardiology · 2025Review
- PTEN Regulates Myofibroblast Activation in Valvular Interstitial Cells Based on Subcellular Localization.Advanced biology · 2025Article
- A Review on the Role of DNA Methylation in Aortic Disease Associated With Marfan Syndrome.Cardiology research · 2025Review
- Epigenetic crossroads in metabolic and cardiovascular health: the role of DNA methylation in type 2 diabetes and cardiovascular diseases.Cardiovascular diabetology · 2025Review
- DNA Methyltransferases 1-Regulated Methylation of Protein Kinase C Zeta Influences Its Expression in Breast Cancer Cells.Journal of breast cancer · 2025Article
- Diabetes-Driven Atherosclerosis: Updated Mechanistic Insights and Novel Therapeutic Strategies.International journal of molecular sciences · 2025Review
- The functional significance of vascular DNA hypermethylation in atherosclerosis: a historical perspective.Frontiers in pharmacology · 2025Review
- Epigenetic regulation in coronary artery disease: from mechanisms to emerging therapies.Frontiers in molecular biosciences · 2025Review
- Epigenetic modification of CD4Cell death & disease · 2024Article
- PTEN: an emerging target in rheumatoid arthritis?Cell communication and signaling : CCS · 2024Review
- Nuclear Control of Vascular Smooth Muscle Cell Plasticity during Vascular Remodeling.The American journal of pathology · 2024Review
- DNA methylation and histone post-translational modifications in atherosclerosis and a novel perspective for epigenetic therapy.Cell communication and signaling : CCS · 2023Review
- Dedifferentiation andMolecular medicine reports · 2022Review
- Exploration of the shared gene signatures and molecular mechanisms between atherosclerosis and rheumatoid arthritis via multi-microarray data analyses.Annals of translational medicine · 2022Article
- Heterogeneous subpopulations of adventitial progenitor cells regulate vascular homeostasis and pathological vascular remodelling.Cardiovascular research · 2022Review
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveOur recent work demonstrates that PTEN (phosphatase and tensin homolog) is an important regulator of smooth muscle cell (SMC) phenotype. SMC-specific PTEN deletion promotes spontaneous vascular remodeling and PTEN loss correlates with increased atherosclerotic lesion severity in human coronary arteries. In mice, PTEN overexpression reduces plaque area and preserves SMC contractile protein expression in atherosclerosis and blunts Ang II (angiotensin II)-induced pathological vascular remodeling, suggesting that pharmacological PTEN upregulation could be a novel therapeutic approach to treat vascular disease. Approach and Results: To identify novel PTEN activators, we conducted a high-throughput screen using a fluorescence based PTEN promoter-reporter assay. After screening ≈3400 compounds, 11 hit compounds were chosen based on level of activity and mechanism of action. Following in vitro confirmation, we focused on 5-azacytidine, a DNMT1 (DNA methyltransferase-1) inhibitor, for further analysis. In addition to PTEN upregulation, 5-azacytidine treatment increased expression of genes associated with a differentiated SMC phenotype. 5-Azacytidine treatment also maintained contractile gene expression and reduced inflammatory cytokine expression after PDGF (platelet-derived growth factor) stimulation, suggesting 5-azacytidine blocks PDGF-induced SMC de-differentiation. However, these protective effects were lost in PTEN-deficient SMCs. These findings were confirmed in vivo using carotid ligation in SMC-specific PTEN knockout mice treated with 5-azacytidine. In wild type controls, 5-azacytidine reduced neointimal formation and inflammation while maintaining contractile protein expression. In contrast, 5-azacytidine was ineffective in PTEN knockout mice, indicating that the protective effects of 5-azacytidine are mediated through SMC PTEN upregulation.
conclusionsOur data indicates 5-azacytidine upregulates PTEN expression in SMCs, promoting maintenance of SMC differentiation and reducing pathological vascular remodeling in a PTEN-dependent manner.
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