Université Clermont Auvergne, INRAE, UNH, F-63000 Clermont-Ferrand, France.
Division of Cardiovascular Medicine, University of California Davis, 95616 Davis, CA, USA.
J Proteomics. 2022 Jul 15;263:104603. doi: 10.1016/j.jprot.2022.104603. Epub 2022 May 12.
Dysfunction of blood-brain barrier formed by endothelial cells of cerebral blood vessels, plays a key role in development of neurodegenerative disorders. Epicatechin exerts vasculo-protective effects through genomic modifications, however molecular mechanisms of action, particularly on brain endothelial cells, are largely unknow. This study aimed to use a multi-omic approach (transcriptomics of mRNA, miRNAs and lncRNAs, and proteomics), to provide novel in-depth insights into molecular mechanisms of how metabolites affect brain endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological concentrations. We showed that metabolites can simultaneously modulate expression of protein-coding, non-coding genes and proteins. Integrative analysis revealed interactions between different types of RNAs and form functional groups of genes involved in regulation of processing like VEGF-related functions, cell signaling, cell adhesion and permeability. Molecular modeling of genomics data predicted that metabolites decrease endothelial cell permeability, increased by lipotoxic stress. Correlation analysis between genomic modifications observed and genomic signature of patients with vascular dementia and Alzheimer's diseases showed opposite gene expression changes. Taken together, this study describes for the first time a multi-omic mechanism of action by which (-)-epicatechin metabolites could preserve brain vascular endothelial cell integrity and reduce the risk of neurodegenerative diseases. SIGNIFICANCE: Dysfunction of the blood-brain barrier (BBB), characterized by dysfunction of endothelial cells of cerebral blood vessels, result in an increase in permeability and neuroinflammation which constitute a key factor in the development neurodegenerative disorders. Even though it is suggested that polyphenols can prevent or delay the development of these disorders, their impact on brain endothelial cells and underlying mechanisms of actions are unknow. This study aimed to use a multi-omic approach including analysis of expression of mRNA, microRNA, long non-coding RNAs, and proteins to provide novel global in-depth insights into molecular mechanisms of how (-)-epicatechin metabolites affect brain microvascular endothelial cells under lipid-stressed (as a model of BBB dysfunction) at physiological relevant conditions. The results provide basis of knowledge on the capacity of polyphenols to prevent brain endothelial dysfunction and consequently neurodegenerative disorders.
血脑屏障功能障碍是由脑血管内皮细胞引起的，在神经退行性疾病的发展中起着关键作用。表儿茶素通过基因组修饰发挥血管保护作用，但其作用机制，特别是对脑内皮细胞的作用机制，在很大程度上尚不清楚。本研究旨在采用多组学方法（mRNA、miRNA 和 lncRNA 的转录组学和蛋白质组学），提供关于代谢物在生理相关条件下（作为血脑屏障功能障碍模型）如何影响脂质应激下的脑内皮细胞的分子机制的新的深入见解。我们表明，代谢物可以同时调节蛋白质编码、非编码基因和蛋白质的表达。综合分析揭示了不同类型的 RNA 之间的相互作用，并形成了与血管内皮生长因子相关功能、细胞信号转导、细胞黏附和通透性等加工调节相关的功能基因群。基因组数据的分子建模预测，代谢物可以降低内皮细胞的通透性，而脂质毒性应激会增加通透性。观察到的基因组修饰与血管性痴呆和阿尔茨海默病患者基因组特征之间的相关性分析显示出相反的基因表达变化。总之，本研究首次描述了（-）-表儿茶素代谢物通过何种多组学作用机制来保护脑血管内皮细胞的完整性并降低神经退行性疾病的风险。意义：血脑屏障（BBB）功能障碍，其特征是脑血管内皮细胞功能障碍，导致通透性增加和神经炎症，这是神经退行性疾病发展的关键因素。尽管多酚被认为可以预防或延缓这些疾病的发展，但它们对脑内皮细胞的影响及其作用机制尚不清楚。本研究旨在采用多组学方法，包括对 mRNA、microRNA、长非编码 RNA 和蛋白质表达的分析，提供关于（-）-表儿茶素代谢物在生理相关条件下（作为 BBB 功能障碍模型）影响脂质应激下脑微血管内皮细胞的分子机制的新的深入见解。研究结果为多酚预防脑内皮功能障碍进而预防神经退行性疾病的能力提供了知识基础。
