Endothelial Sphingolipid Synthesis and Tissue Inflammatory Response

内皮鞘脂合成和组织炎症反应

• 批准号: 10318522
• 负责人: Annarita Di Lorenzo
• 金额: $ 45.68万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-11 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318522
• 关键词: Address; Anabolism; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Binding; Blood Pressure; Blood Vessels; Cause of Death; Cell Nucleus; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Development; Disease; Economic Burden; Endoplasmic Reticulum; Endothelium; Enzymes; G-Protein-Coupled Receptors; Gene Activation; Genetic Transcription; Goals; Grant; Heart failure; Homeostasis; Human; Hypertension; Inflammation; Inflammatory; Inflammatory Response; Injury; Knock-out; Knockout Mice; Medical; Membrane Proteins; Metabolism; Modeling; Mortality Determinants; Mus; Myocardial; Myocardial Infarction; Names; Operative Surgical Procedures; Pathogenesis; Pathologic; Pathway interactions; Pharmacology; Phosphorylation; Predisposition; Process; Production; Public Health; Reporter; Reporting; Research; Resistance; Role; Rupture; Signal Transduction; Site; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stimulus; Stress; TNF gene; Therapeutic; Tissues; Vascular Diseases; atheroprotective; base; coronary lesion; coronary plaque; drug discovery; hemodynamics; human disease; in vivo; innovation; lipid mediator; mouse model; novel; oxidized low density lipoprotein; pressure; serine palmitoyltransferase; sphingosine 1-phosphate; therapeutic target; transcriptome; vascular inflammation

Endothelial injury promotes the development of atherosclerosis at the site of disturbed flow. Sphingosine-1-phosphate (S1P), produced by sphingolipid metabolism, is a secreted lipid mediator that interacts with G protein-coupled receptors, named S1P1-5. Locally produced and circulating S1P activate S1P receptors, particularly S1P1 the most abundant in the endothelium, to maintain vascular homeostasis. Altered sphingolipid metabolism and S1P signaling has been implicated in vascular disease, including coronary artery diseases (CAD). The current grant led to several advances. First, we discovered a novel mechanism by which endothelial sphingolipid biosynthesis is regulated. Nogo-B, a membrane protein of the ER, highly expressed in blood vessels, binds to and inhibits serine palmitoyltransferase (SPT), the rate-limiting enzyme of the de novo sphingolipid production. Second, we revealed that Nogo-B/SPT interaction downregulates local S1P signaling contributing to inflammation, hypertension and heart failure. Third, we found that inflammatory stimuli and ox-LDL induce Nogo-B phosphorylation, which further inhibits SPT activity contributing to endothelial injury. Fourth, following TNF-α, the N-terminus of Nogo-B is cleaved and translocates to the nucleus to impact endothelial transcriptome. Our long-term goal is to understand how Nogo-B regulates local sphingolipid signaling and its impact on coronary functions in the pathogenesis of CAD. Our hypothesis is that Nogo-B controls endothelial-derived S1P signaling, which is a key regulator of vascular homeostasis and disease- thereby influencing coronary plaque progression. Mechanistically, we hypothesize that Nogo-B promotes vascular inflammation and diseases via two major mechanisms; SPT inhibition, thus disrupting locally-derived S1P signaling, and the activation of gene profile. The rational is that the discovery of new mechanisms regulating endothelial inflammation will provide potential therapeutic targets for CAD. For the renewal, we propose to: 1) Investigate the role of endothelial Nogo-B in the susceptibility of mice to coronary atherosclerosis; 2) Determine the importance of endothelial S1P signaling and its role as downstream effector of Nogo-B in the onset of coronary atherosclerosis; 3) Dissecting the mechanism of Nogo-B signaling in myocardial endothelial injury. This contribution is significant since will identify novel targets for the treatment of CAD, especially since available therapies have been only partially successful, and beyond the statins, there are currently no effective pharmacological strategies that effectively address vascular inflammation. The proposed research is innovative because we investigate the effects of altered sphingolipid homeostasis and S1P signaling on the progression of coronary atherosclerosis, by using a novel mouse model of CAD and myocardial infarction that better recapitulates the human disease, a heretofore-unexamined process.

内皮损伤促进血流紊乱部位动脉粥样硬化的发展。 鞘氨醇-1-磷酸（S1 P）由鞘脂代谢产生，是一种分泌的脂质介质， 与G蛋白偶联受体相互作用，命名为S1 P1 -5。当地生产和流通的S1 P 激活S1 P受体，特别是内皮中最丰富的S1 P1，以维持血管 体内平衡鞘脂代谢和S1 P信号转导的改变与血管内皮细胞的生长和分化有关。 疾病，包括冠状动脉疾病（CAD）。目前的赠款导致了几项进展。一是 发现了一种调节内皮鞘脂生物合成的新机制。Nogo-B，a ER的膜蛋白，在血管中高度表达，结合并抑制丝氨酸 棕榈酰转移酶（SPT），从头鞘脂生产的限速酶。第二、 我们发现Nogo-B/SPT相互作用下调了局部S1 P信号传导， 炎症高血压和心力衰竭第三，我们发现炎症刺激和ox-LDL 诱导Nogo-B磷酸化，从而进一步抑制导致内皮损伤的SPT活性。 第四，在TNF-α之后，Nogo-B的N-末端被切割并易位到细胞核，以影响细胞内的蛋白质。 内皮转录组。我们的长期目标是了解Nogo-B如何调节局部鞘脂 信号传导及其在CAD发病机制中对冠状动脉功能的影响。我们的假设是 Nogo-B控制内皮源性S1 P信号传导，这是血管稳态的关键调节因子 和疾病-从而影响冠状动脉斑块的进展。从机制上讲，我们假设 Nogo-B通过两种主要机制促进血管炎症和疾病; SPT抑制， 破坏局部来源的S1 P信号传导和基因谱的激活。合理的解释是 发现调节内皮炎症的新机制将提供潜在的治疗 CAD的目标为了更新，我们建议：1）研究内皮Nogo-B在血管内皮细胞中的作用， 小鼠对冠状动脉粥样硬化的易感性; 2）确定内皮S1 P的重要性 信号传导及其作为Nogo-B下游效应物在冠状动脉粥样硬化发病中的作用; 3） 探讨Nogo-B信号在心肌内皮损伤中的作用机制。 这一贡献是重要的，因为将确定治疗CAD的新靶点，特别是因为 现有的治疗方法只有部分成功，除了他汀类药物，目前没有 有效治疗血管炎症的有效药理学策略。拟议 这项研究是创新的，因为我们研究了改变鞘脂稳态和S1 P的影响， 冠状动脉粥样硬化进展的信号传导，通过使用一种新的CAD小鼠模型， 心肌梗死，更好地概括了人类疾病，一个迄今为止未经审查的过程。