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

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

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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.

肥胖和代谢的个体中，心血管疾病（例如动脉粥样硬化）的复杂性疾病和心血管疾病紧密相关。部分原因是肥胖流行病疾病仍然是我国死亡率的最高原因。该项目的目的是了解如何脂肪组织直接围绕血管，血管周围脂肪组织（PVAT）调节血管微环境。在肥胖期间，PVAT扩展并变得功能失调，我们建议这些变化建立了促进血管疾病的可动脉粥样硬化感的环境。在初步研究中，我们已经分析了人类和小鼠PVAT，发现Notch信号的水平升高。这是真的人类PVAT来自患有冠状动脉搭桥的晚期血管疾病的患者嫁接手术以及喂养高脂肪饮食的小鼠。我们假设在肥胖症或高脂肪喂养条件下的PVAT会导致SIRT蛋白质的变化，从而影响从PVAT到血管壁的旁分泌因子的分泌。我们检验该假设的方法包括对人类PVAT的深入蛋白质组学研究，该研究来自具有不同阶段血管疾病的个体，以及对动脉粥样硬化小鼠模型中PVAT的相应分析。该项目的目的是：特定目的1。确定定义动脉粥样硬化的人和小鼠PVAT的独特蛋白质特征相对于动脉敏感的微环境。我们将在调节的PVAT分泌组中定义新的目标在高脂肪饮食和动脉粥样硬化条件下的血管细胞。确定的目标是保护性或可能加剧血管功能障碍，将直接测试对体外血管细胞的影响。具体目的2。确定肥胖期间PVAT中升高的Notch信号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，并将其结合起来使用ApoE Null小鼠进行高脂肪饮食，以研究对PVAT生物学和动脉粥样硬化的影响。 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。可以通过交叉引用更改来识别唯一的缺口目标在AIM 1中确定的蛋白质特征中。最后，PVAT脂肪细胞祖细胞及其分化能力将在不同的高脂饮食条件下进行特征，导致动脉粥样硬化。特定目的3。评估肥胖期间SIRT基因的Notch调节的假设有助于 PVAT表型的变化及其对血管壁的旁分泌信号传导活性。我们将使用体内分析使用来自冠状动脉搭桥手术的人类PVAT，肥胖小鼠模型和从缺口活性和代谢状态不同的小鼠的分离的PVAT进行的离体研究。