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

• 批准号: 9977874
• 负责人: Lucy Liaw
• 金额: $ 50.93万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 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/9977874
• 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; Endothelium; Environment; 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; Obesity Epidemic; 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 genetics; mouse model; notch protein; novel; paracrine; progenitor; proteomic signature; response

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.

心血管疾病，如动脉粥样硬化，在肥胖和代谢紊乱的个体中是复杂的。 疾病和心血管疾病紧密相连。部分原因是肥胖流行，心血管疾病 疾病仍然是我国最高的死亡原因。这个项目的目标是了解如何 直接围绕血管的脂肪组织，即血管周围脂肪组织（PVAT），调节血管 微环境在肥胖期间，PVAT扩大并变得功能失调，我们建议这些 这些变化建立了一个动脉粥样硬化易感环境，促进血管疾病。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。是如此 来自接受冠状动脉搭桥术的晚期血管疾病患者的人PVAT 移植手术，以及高脂肪饮食的小鼠。我们假设，在细胞中的组成性Notch信号转导， 肥胖或高脂喂养条件下的PVAT导致Sirt蛋白的变化，这反过来又影响 旁分泌因子从PVAT分泌到血管壁。我们测试这一假设的方法包括 来自不同阶段血管疾病个体的人PVAT的深入蛋白质组学研究， 以及小鼠动脉粥样硬化模型中PVAT的相应分析。该项目的目标是： 具体目标1.确定人类和小鼠PVAT的独特蛋白质特征，定义抗动脉粥样硬化 与动脉粥样硬化易感微环境的对比。我们将在PVAT分泌组中定义新的靶点， 血管细胞在高脂饮食和动脉粥样硬化的条件下。确定的目标可能是 保护或可能加重血管功能障碍的药物将在体外直接测试对血管细胞的影响。 具体目标2。确定肥胖期间PVAT中Notch信号的升高如何影响其表型， 血管疾病我们将使用小鼠遗传学方法来改变PVAT中的Notch信号传导，并将其联合收割机 用高脂肪饮食的ApoE敲除小鼠研究对PVAT生物学和动脉粥样硬化形成的影响。PVAT 表型将基于棕色、米色或白色脂肪样的身份进行评估; 脂肪因子产生和炎症。可通过交叉引用变更来识别独特的Notch目标 在目标1中鉴定的蛋白质特征中。最后，PVAT脂肪祖细胞及其分化能力 将在导致动脉粥样硬化的不同高脂肪饮食条件下表征。 具体目标3。评估肥胖期间Sirt基因的Notch调控有助于 PVAT表型的变化及其对血管壁的旁分泌信号传导活性。我们将在体内利用 使用源自冠状动脉旁路移植手术的人PVAT、肥胖小鼠模型和 用来自Notch活性和代谢状态不同的小鼠的分离的PVAT进行离体研究。