Understanding the Contribution of Endothelial Lipid Droplet Metabolism in Cardiovascular Diseases

了解内皮脂滴代谢在心血管疾病中的作用

• 批准号: 10687412
• 负责人: Boa Kim
• 金额: $ 5.55万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2023-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687412
• 关键词: Ablation; Adipose tissue; Affect; Atherosclerosis; Biological Assay; Biology; Blood Vessels; CCL2 gene; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cause of Death; Cell Culture Techniques; Data; Disease Progression; Down-Regulation; Endothelial Cells; Endothelium; Enzymes; Fatty acid glycerol esters; Forskolin; Genetic; Health; Hydrolysis; Hypertension; Impairment; In Vitro; Inflammatory; Intake; Knockout Mice; Lead; Lipase; Lipid Binding; Lipids; Lipolysis; Luciferases; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Monitor; Mus; Myography; NF-kappa B; NOS3 gene; Obesity; Organelles; Pathogenesis; Pathologic; Pathway interactions; Pharmacology; Population; Production; Proteins; Proteomics; Public Health; Reporter; Role; Signal Transduction; Small Interfering RNA; Sodium Chloride; System; Telemetry; Testing; Triglycerides; United States; Vascular Diseases; Vasodilator Agents; Western Blotting; base; blood pressure elevation; cardiovascular health; chemokine; diacylglycerol O-acyltransferase; endothelial dysfunction; epidemiology study; hypercholesterolemia; in vivo; in vivo evaluation; inhibitor; insight; knockout animal; neutralizing antibody; novel; novel therapeutic intervention; overexpression; pressure; transcriptome sequencing; vascular bed

Project Summary/Abstract Components of the metabolic syndrome are interconnected in a way that remains poorly understood. Obesity and hypertension are, for example, highly correlated. However, how obesity or fat intake increases blood pressure is unclear. The presence of lipid droplets (LDs) has been observed in endothelial cells (ECs) under pathological conditions. Surprisingly, however, LD biology in ECs is little studied and how altered endothelial LD metabolism affects health is entirely unknown. We now find, in preliminary data, that endothelial LDs likely contribute significantly to the progression of cardiovascular disease. To test the role of LDs in the endothelium, we have generated EC-specific adipose triglyceride lipase (ATGL) (the rate-limiting enzyme in TG hydrolysis) knockout (KO) mice. The ATGL ECKO mice had LD accumulation in numerous vascular beds and were predisposed to multiple cardiovascular diseases including hypertension and atherosclerosis. Strikingly, expression of endothelial nitric oxide synthase (eNOS), a dominant vasodilator that protects against hypertension and atherosclerosis, was suppressed in ATGL-deficient ECs both in cell culture and in vivo. eNOS expression was restored by reducing LD contents, either by increasing lipolysis or decreasing TG synthesis. These data strongly suggest that LDs are causal to the compromised eNOS expression, and led us to hypothesize that endothelial LD accumulation causes vascular dysfunction and cardiovascular disease and propose the following two aims: Aim1. To test in vivo whether LDs are responsible for impaired vasoreactivity, hypertension and atherosclerosis seen in ATGL ECKO mice by using genetic ablation of enzymes that promote TG synthesis, which we have shown to be sufficient to rescue LD content in vitro. Aim2. To investigate the mechanism by which LD accumulation leads to endothelial dysfunction. We hypothesize the existence of a LD – NF-kB – MCP1 axis as a novel mechanism for impaired eNOS expression and endothelial dysfunction in ATGL-deficient ECs. This study will elucidate largely unknown endothelial LD biology in the context of cardiovascular and metabolic disease and provide fundamental insight into the poorly understood relationship between metabolic syndrome and vascular complications of cardiovascular disease.

项目总结/摘要 代谢综合征的组成部分是相互联系的方式仍然知之甚少。肥胖 和高血压是高度相关的然而，肥胖或脂肪摄入如何增加血液 压力不明确。脂质滴（LD）的存在已在内皮细胞（EC）中观察到， 病理条件。然而，令人惊讶的是，内皮细胞中的LD生物学研究很少， 新陈代谢影响健康是完全未知的。 我们现在发现，在初步的数据中，内皮LD可能显著促进了 心血管疾病为了测试LD在内皮中的作用，我们已经产生了EC特异性脂肪细胞。 甘油三酯脂肪酶（ATGL）（TG水解中的限速酶）敲除（KO）小鼠。ATGL ECKO 小鼠在许多血管床中有LD积聚，并且易于发生多种心血管疾病 包括高血压和动脉粥样硬化。值得注意的是，内皮型一氧化氮合酶（eNOS）的表达， 一种主要的血管扩张剂，可以防止高血压和动脉粥样硬化，在ATGL缺乏的患者中受到抑制。 细胞培养和体内的EC。eNOS表达通过降低LD含量，或通过增加 脂肪分解或减少TG合成。这些数据有力地表明LD是导致eNOS受损的原因 表达，并使我们假设内皮LD积累导致血管功能障碍， 心血管疾病，并提出以下两个目标：目标1。为了在体内测试LD是否负责 对于使用基因消融在ATGL ECKO小鼠中观察到的血管反应性受损、高血压和动脉粥样硬化， 促进TG合成的酶，我们已经证明这足以在体外拯救LD含量。 目标2。探讨LD蓄积导致内皮功能障碍的机制。我们 假设存在LD-NF-kB-MCP 1轴作为eNOS表达受损的新机制 以及ATGL缺陷EC中的内皮功能障碍。 这项研究将阐明在心血管和代谢的背景下， 疾病，并提供基本的洞察力，了解代谢综合征之间的关系知之甚少， 以及心血管疾病的血管并发症。