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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要代谢综合征的各个组成部分之间的相互关联性目前仍知之甚少。例如，肥胖或脂肪摄入如何增加血液是高度相关的。压力下的内皮细胞（EC）中是否存在脂滴（LD）尚不清楚。然而，令人惊讶的是，EC 中的 LD 生物学以及内皮 LD 是如何改变的却很少被研究。新陈代谢对健康的影响完全未知。我们现在发现，在初步数据中，内皮 LD 可能对疾病的进展有显着贡献。为了测试 LD 在内皮细胞中的作用，我们生成了 EC 特异性脂肪。甘油三酯脂肪酶 (ATGL)（TG 水解中的限速酶）敲除 (KO) 小鼠。小鼠的许多血管床中都有LD积累，易患多种心血管疾病值得注意的是，内皮一氧化氮合酶（eNOS）的表达，包括高血压和动脉粥样硬化。血管扩张剂可预防高血压和动脉粥样硬化，但在 ATGL 缺陷者中受到抑制细胞培养物和体内的 eNOS 表达均通过降低 LD 含量或增加来恢复。这些数据强烈表明 LD 是 eNOS 受损的原因。表达，并导致我们追查内皮LD积累导致血管功能障碍和心血管疾病并提出以下两个目标：目的1. 体内测试LDs是否负责。通过基因消融治疗 ATGL ECKO 小鼠中发现的血管反应性受损、高血压和动脉粥样硬化促进 TG 合成的酶，我们已证明这些酶足以在体外挽救 LD 含量。目的2.研究LD积累导致内皮功能障碍的机制。保留了 LD – NF-kB – MCP1 轴的存在，作为 eNOS 表达受损的新机制 ATGL 缺陷的 EC 中的内皮功能障碍。这项研究将阐明心血管和代谢背景下很大程度上未知的内皮 LD 生物学疾病并提供对代谢综合征之间鲜为人知的关系的基本见解和心血管疾病的血管并发症。