Understanding the Contribution of Endothelial Lipid Droplet Metabolism in Cardiovascular Diseases

项目摘要/摘要 代谢综合征的组成部分以一种仍然知之甚少的方式相互关联。肥胖 例如，与高血压高度相关。然而，肥胖或脂肪摄入是如何增加血液的 目前尚不清楚压力大小。在体外培养的血管内皮细胞(ECs)中观察到脂滴的存在。 病理情况。然而，令人惊讶的是，内皮细胞中的LD生物学研究很少，以及内皮LD是如何改变的 新陈代谢对健康的影响是完全未知的。 我们现在发现，在初步数据中，内皮细胞LDs可能对血管病变的进展有重要贡献 心血管疾病。为了测试LDS在内皮细胞中的作用，我们产生了EC特异性脂肪 甘油三酯脂肪酶(ATGL)(甘油三酯水解的限速酶)基因敲除(KO)小鼠。ATGL ECKO 小鼠在众多血管床上积聚乳酸，易患多种心血管疾病 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)a的表达 保护高血压和动脉粥样硬化的优势血管扩张剂在ATGL缺乏的患者中受到抑制 无论是在细胞培养中还是在体内都存在ECS。通过减少LD含量来恢复eNOS的表达，无论是通过增加 脂肪分解或甘油三酯合成减少。这些数据有力地表明LDS是eNOS受损的因果关系 表达，并导致我们假设内皮性LD积聚导致血管功能障碍和 并提出以下两个目标：AIM1。为了在体内测试LDS是否对 ATGL ECKO小鼠血管反应性受损、高血压和动脉粥样硬化的基因消融 促进甘油三酯合成的酶，我们已经证明在体外足以挽救LD的含量。 AIM2.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-MCP1轴作为eNOS表达受损的新机制 ATGL缺陷内皮细胞的内皮功能障碍。 这项研究将在心血管和代谢的背景下阐明很大程度上未知的内皮LD生物学 并提供了对代谢综合征之间鲜为人知的关系的基本见解 以及心血管疾病的血管并发症。

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.