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首页> 外文期刊>Arteriosclerosis, thrombosis, and vascular biology >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
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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

机译：高通量筛网识别DNMT1（DNA甲基转移酶-1）抑制剂，5-氮杂胞苷，作为PTEN（磷酸酶和牙素同源物）的有效诱导剂，用于PTEN在5-氮杂胞苷保护免受病理血管改造的情况下

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Objective: Our 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 approximate to 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. Conclusions: Our data indicates 5-azacytidine upregulates PTEN expression in SMCs, promoting maintenance of SMC differentiation and reducing pathological vascular remodeling in a PTEN-dependent manner.
机译：目的：我们最近的工作表明，PTEN（磷酸酶和抗素同源物）是平滑肌细胞（SMC）表型的重要调节因子。 SMC特异性PTEN缺失促进自发血管重塑，PTEN损失与人冠状动脉中的动脉粥样硬化病变严重程度增加相关。在小鼠中，PTEN过度表达减少了斑块区域，并保留了动脉粥样硬化中的SMC收缩蛋白表达，并钝了ANG II（血管紧张素II） - 诱导的病理血管重塑，表明药理学PTEN上调可能是治疗血管疾病的新疗法方法。方法和结果：为了鉴定新型PTEN激活剂，我们使用基于荧光的PTEN启动子报告结果进行高通量筛网。在筛选近似为3400化合物后，基于活性水平和作用机制选择11个麦芽化合物。在体外确认之后，我们专注于5-氮杂胞苷，DNMT1（DNA甲基转移酶-1）抑制剂，用于进一步分析。除了PTEN上调外，5-氮杂胞苷治疗还增加了与分化的SMC表型相关的基因的表达。 5-氮杂胞苷治疗还保持收缩基因表达和PDGF（血小板衍生的生长因子）刺激后降低的炎症细胞因子表达，表明5-氮杂胞苷嵌段PDGF诱导的SMC脱差。然而，这些保护作用在PTEN缺陷的SMC中丧失。使用用5-氮杂胞苷处理的SMC特异性PTEN敲除小鼠中的颈动脉结扎在体内确认这些发现。在野生型对照中，5-氮杂胞苷减少新内膜形成和炎症，同时保持收缩蛋白表达。相比之下，5-氮杂胞苷在Pten敲除小鼠中无效，表明5-氮杂胞苷的保护作用通过SMC PTEN上调介导。结论：我们的数据表明，5-氮杂胞苷上调SMC中的PTEN表达，促进SMC分化的维持，并以PTEN依赖性方式降低病理血管重塑。

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