Insights into the molecular mechanisms regulating vascular and immune metabolism in vascular diseases

项目总结 动脉粥样硬化是一种以血脂为特征的慢性疾病，是心血管疾病的主要病因。 滞留和血管炎症。内皮细胞(ECs)、平滑肌细胞(SMC)和巨噬细胞 都被认为对疾病的发展有独特的影响。最近人们认识到，特定的 代谢信号通路的失调与EC、巨噬细胞和SMC的某些方面有关 动态平衡。例如，在动脉粥样硬化的过程中，内皮细胞暴露在促炎因子中。 促进糖酵解和减少内皮细胞中脂肪酸氧化的环境，并使它们容易经历 间充质转化(EndMT)，这可能影响斑块的稳定性。非编码RNA的含义， 包括microRNAs(MiRNAs)，在心血管疾病中是公认的，代表最快 不断发展的研究领域。此外，miRNAs已经成为细胞新陈代谢的关键调节因子(例如， MIR-33)，因此可以直接调节EC的代谢反应，从而决定肿瘤的进展 动脉粥样硬化，尽管这一方面尚未阐明。此外，miRNAs可以促进 获得间充质标志物(例如miR-21)，这些标志物反过来可以塑造它们的代谢反应和 间充质表型，从而影响EC动脉粥样硬化表型。这件事也没有被调查 详细地说。在这方面，SMC的表型调控可能涉及类似的机制。 动脉粥样硬化，也需要探索。大量文献表明，miRNAs在 巨噬细胞炎症反应与巨噬细胞功能的重要调控 脂类代谢。越来越多的证据表明，与生俱来的免疫之间存在着实质性的串扰 信号和代谢途径。巨噬细胞的激活和分化是其显著特征 参与一般细胞代谢活动的基因的调节。在这方面，下调监管 经典激活的巨噬细胞中的胆固醇生物合成基因与炎症的调节有关 巨噬细胞引发的反应。一个关键的悬而未决的问题是， 胆固醇、胆固醇生物合成中间体和胆固醇衍生物影响巨噬细胞泡沫 细胞形成和炎症，这是动脉粥样硬化进展的关键决定因素。总体而言， 这项研究计划旨在阐明调节细胞特定代谢信号的不同机制。 途径以及它们如何参与动脉粥样硬化的进展。靶向细胞特异性代谢 PROCESS可能成为治疗代谢紊乱的另一种潜在的治疗靶向策略。

PROJECT SUMMARY Atherosclerosis, the major cause of cardiovascular disease (CVD), is a chronic disease characterized by lipid retention and vascular inflammation. Endothelial cells (ECs), smooth muscle cells (SMCs) and macrophages are recognized to have a unique impact on the disease progression. It is recently recognized that specific dysregulation of metabolic signaling pathways contributes to certain aspects of EC, macrophage and SMC homeostasis. For instance, during the process of atherosclerosis, ECs are exposed to a pro-inflammatory milieu that enhances glycolysis and reduces fatty acid oxidation in ECs and predisposes them to undergo mesenchymal transition (EndMT), which may affect plaque stability. The implications of non-coding RNAs, including microRNAs (miRNAs), in cardiovascular disease is well recognized, representing the most rapidly evolving research field. Furthermore, miRNAs have emerged as critical regulators of cellular metabolism (e.g. miR-33) and therefore can directly regulate EC metabolic responses that can determine the progression of atherosclerosis, although this aspect has not been elucidated yet. Moreover, miRNAs can promote the acquisition of mesenchymal markers (e.g. miR-21) that can in turn shape their metabolic response and mesenchymal phenotype, thus affecting EC atherosclerotic phenotype. This has also not been investigated in detail. In this regard, similar mechanisms may be involved in the phenotypic regulation of SMC during atherosclerosis, and need to be explored as well. A vast literature has demonstrated that miRNAs play important roles in macrophage functions by regulating macrophage inflammatory responses and lipid metabolism. Increasing evidence indicates that a substantial crosstalk exists between innate immune signaling and metabolic pathways. Macrophage activation and differentiation prominently feature the modulation of genes involved in general cellular metabolic activities. In this regard, downregulation of cholesterol biosynthetic genes in classically activated macrophages is linked to regulation of inflammatory reactions elicited by macrophages. A critical outstanding question is how the dynamic interplay between cholesterol, cholesterol biosynthetic intermediates and cholesterol derivatives influences macrophage foam cell formation and inflammation, which are key determinants of atherosclerosis progression. On the whole, this research program aims to elucidate different mechanisms that regulate cell-specific metabolic signaling pathways and how they are involved in the progression of atherosclerosis. Targeting cell-specific metabolic processes could become another potential therapeutic targeting strategy for treating metabolic disorders.