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首页> 外文期刊>Biochemical Pharmacology >(-)-Epicatechin metabolites promote vascular health through epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation
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(-)-Epicatechin metabolites promote vascular health through epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation

机译：（ - ） - EPICATECHIN代谢物通过内皮 - 免疫细胞信号传导的表观遗传重编程促进血管健康，并逆转全身低级炎症

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Ingestion of (-)-epicatechin flavanols reverses endothelial dysfunction by increasing flow mediated dilation and by reducing vascular inflammation and oxidative stress, monocyte-endothelial cell adhesion and transendothelial monocyte migration in vitro and in vivo. This involves multiple changes in gene expression and epigenetic DNA methylation by poorly understood mechanisms. By in silico docking and molecular modeling we demonstrate favorable binding of different glucuronidated, sulfated or methylated (-)-epicatechin metabolites to different DNA methyltransferases (DNMT1/DNMT3A). In favor of this model, genome-wide DNA methylation profiling of endothelial cells treated with TNF and different (-)-epicatechin metabolites revealed specific DNA methylation changes in gene networks controlling cell adhesion-extravasation endothelial hyperpermeability as well as gamma-aminobutyric acid, renin-angiotensin and nitric oxide hypertension pathways. Remarkably, blood epigenetic profiles of an 8 weeks intervention with monomeric and oligomeric flavanols (MOF) including (-)-epicatechin in male smokers revealed individual epigenetic gene changes targeting similar pathways as the in vitro exposure experiments in endothelial cells. Furthermore, epigenetic changes following MOF diet intervention oppose atherosclerosis associated epigenetic changes. In line with biological data, the individual epigenetic response to a MOF diet is associated with different vascular health parameters (glutathione peroxidase 1 and endothelin-1 expression, acetylcholine-mediated microvascular response), in part involving systemic shifts in blood immune cell types which reduce the neutrophil-lymphocyte ratio (NLR). Altogether, our study suggests that different (-)-epicatechin metabolites promote vascular health in part via epigenetic reprogramming of endothelial-immune cell signaling and reversing systemic low-grade inflammation.
机译：摄入（ - ） - EPICATECHIN Flavanols通过增加流量介导的扩张并通过减少体外和体内的血管炎症和氧化应激，单核细胞内皮细胞粘附和横皮学单核细胞迁移来反转内皮功能障碍。这涉及通过理解机制差异的基因表达和表观遗传DNA甲基化的多种变化。通过在硅基硅对接和分子模型中，我们证明了不同葡萄糖化，硫酸化或甲基化（ - ） - EPICATECHIN代谢物与不同DNA甲基转移酶（DNMT1 / DNMT3A）的有利结合。有利于这种模型，用TNF和不同（ - ） - EPICATECHIN代谢物处理的内皮细胞的基因组DNA甲基化分析显示了基因网络中的特异性DNA甲基化变化，控制细胞粘附后内皮高温术和γ-氨基丁酸，肾素 - angiotensin和一氧化氮高血压途径。值得注意的是，血液表观遗传谱的血液表观遗传谱与雄性吸烟者中的单体和低聚类黄烷醇（MOF）（MOF）介绍了雄性吸烟者中的患者，揭示了靶向与内皮细胞中的体外暴露实验相似的途径的单个表观遗传基因。此外，在MOF饮食干预后的表观遗传变化反对动脉粥样硬化相关的表观遗传变化。根据生物数据，对MOF饮食的个体表观遗传反应与不同的血管健康参数（谷胱甘肽过氧化物酶1和内皮素-1表达，乙酰胆碱介导的微血管反应）有关，部分涉及减少的血液免疫细胞类型的全身变化中性粒细胞淋巴细胞比（NLR）。完全，我们的研究表明，不同（ - ） - EPICATECHIN代谢物部分地通过内皮 - 免疫细胞信号传导的表观遗传重编程促进血管健康，并逆转全身低级炎症。

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