Regulation of arterial phenotype by perivascular adipose tissue in cardiometabolic disease

心脏代谢疾病中血管周围脂肪组织对动脉表型的调节

基本信息

批准号：
9495408
负责人：
Lucy Liaw
金额：
$ 50.62万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9495408
关键词：
Adipocytes Adipose tissue Affect Anatomy Apolipoprotein E Atherosclerosis Biology Blood Vessels Brown Fat Cardiovascular Diseases Cell physiology Cells Characteristics Clinical Coronary Artery Bypass Country Disease Disease Progression Disease susceptibility Endocrine Glands Environment Epidemic Fatty acid glycerol esters Genes Genetic Goals High Fat Diet Human In Vitro Individual Inflammation Knockout Mice Left Light Link Mediator of activation protein Metabolic Metabolic Diseases Metabolic dysfunction Metabolic stress Modeling Molecular Mus Myocardial Infarction Obesity Operative Surgical Procedures Paracrine Communication Pathologic Patients Phenotype Play Predisposition Production Proteins Proteomics Regulation Role Sampling Signal Transduction Sirtuins Smooth Muscle Myocytes Testing Thoracic aorta Tunica Adventitia Vascular Diseases Vasodilation adipokines athero susceptible atherogenesis base cardiometabolism cardiovascular health cardiovascular risk factor feeding genetic approach in vivo mortality mouse model notch protein novel paracrine progenitor proteomic signature response

项目摘要

Cardiovascular diseases such as atherosclerosis are compounded in individuals who are obese, and metabolic disease and cardiovascular diseases are tightly linked. In part due to the obesity epidemic, cardiovascular disease remains the highest cause of mortality in our country. The goal of this project is to understand how adipose tissue directly surrounding blood vessels, perivascular adipose tissue (PVAT), regulates the vascular microenvironment. During obesity, PVAT expands and becomes dysfunctional, and we propose that these changes establish an atherosusceptible environment that promotes vascular disease. In preliminary studies, we have analyzed both human and mouse PVAT and found elevated levels of Notch signaling. This is true in human PVAT derived from patients with advanced vascular disease undergoing coronary artery bypass grafting surgery, as well as in mice fed a high fat diet. We hypothesize that constitutive Notch signaling in PVAT in conditions of obesity or high fat feeding leads to changes in Sirt proteins, which in turn affect the secretion of paracrine factors from PVAT to the vessel wall. Our approaches to test this hypothesis include an in-depth proteomic study of human PVAT derived from individuals with different stages of vascular disease, and corresponding analysis of PVAT in mouse models of atherogenesis. The aims of this project are: Specific Aim 1. Identify unique protein signatures of human and mouse PVAT that define atheroresistant versus atherosusceptible microenvironments. We will define novel targets in the PVAT secretome that regulate vascular cells under conditions of high fat diet and atherogenesis. Identified targets that potentially are protective or could aggravate vascular dysfunction will be tested directly for effects on vascular cells in vitro. Specific Aim 2. Determine how elevated Notch signaling in PVAT during obesity affects its phenotype and vascular disease. We will use a mouse genetic approach to alter Notch signaling in PVAT, and combine that with an ApoE null mouse on a high fat diet to study the effect on PVAT biology and atherogenesis. PVAT phenotype will be assessed based on identity as brown, beige, or white fat-like; and by assessment of adipokine production and inflammation. Unique Notch targets may be identified by cross-referencing changes in protein signatures identified in aim 1. Finally, PVAT adipocyte progenitors and their differentiation capacity will be characterized under different high fat diet conditions leading to atherosclerosis. Specific Aim 3. Evaluate the hypothesis that Notch regulation of Sirt genes during obesity contributes to changes in PVAT phenotype and its paracrine signaling activity to the vessel wall. We will utilize in vivo analysis using human PVAT derived from coronary artery bypass graft surgery, mouse models of obesity, and ex vivo studies with isolated PVAT from mice differing in Notch activity and metabolic state.

肥胖和代谢障碍的个体会加剧动脉粥样硬化等心血管疾病疾病与心血管疾病密切相关。部分原因是肥胖流行、心血管疾病疾病仍然是我国死亡率最高的原因。该项目的目标是了解如何直接围绕血管的脂肪组织，血管周围脂肪组织（PVAT），调节血管微环境。在肥胖期间，PVAT 会扩张并变得功能失调，我们建议这些变化建立了促进血管疾病的动脉粥样硬化环境。在初步研究中，我们分析了人类和小鼠的 PVAT，发现 Notch 信号传导水平升高。这是真实的源自接受冠状动脉搭桥术的晚期血管疾病患者的人类 PVAT 移植手术，以及喂食高脂肪饮食的小鼠。我们假设本构型 Notch 信号传导肥胖或高脂肪喂养条件下的 PVAT 会导致 Sirt 蛋白发生变化，进而影响旁分泌因子从 PVAT 分泌到血管壁。我们检验这一假设的方法包括对来自不同阶段血管疾病个体的人类 PVAT 进行深入的蛋白质组学研究，以及动脉粥样硬化小鼠模型中 PVAT 的相应分析。该项目的目标是：具体目标 1. 识别人类和小鼠 PVAT 定义抗动脉粥样硬化的独特蛋白质特征与动脉粥样硬化易感性微环境相比。我们将在 PVAT 分泌蛋白组中定义新的靶点来调节高脂肪饮食和动脉粥样硬化条件下的血管细胞。已确定的潜在目标保护性或可能加剧血管功能障碍的药物将直接在体外测试对血管细胞的影响。具体目标 2. 确定肥胖期间 PVAT 中 Notch 信号升高如何影响其表型和血管疾病。我们将使用小鼠遗传方法来改变 PVAT 中的 Notch 信号传导，并将其结合起来与高脂肪饮食的 ApoE 缺失小鼠一起研究对 PVAT 生物学和动脉粥样硬化形成的影响。 PVAT 表型将根据棕色、米色或白色脂肪样的身份进行评估；并通过评估脂肪因子的产生和炎症。独特的Notch目标可以通过交叉引用变化来识别目标 1 中确定的蛋白质特征。最后，PVAT 脂肪细胞祖细胞及其分化能力不同的高脂肪饮食条件下都会导致动脉粥样硬化。具体目标 3. 评估肥胖期间 Sirt 基因的 Notch 调节有助于 PVAT 表型及其对血管壁的旁分泌信号活动的变化。我们将利用体内使用源自冠状动脉搭桥手术、肥胖小鼠模型的人类 PVAT 进行分析使用从 Notch 活性和代谢状态不同的小鼠中分离出的 PVAT 进行离体研究。