The Role of Endothelial Cell Mineralocorticoid Receptors in the Development of Vascular Inflammation and Atherosclerosis

内皮细胞盐皮质激素受体在血管炎症和动脉粥样硬化发展中的作用

基本信息

批准号：
9908157
负责人：
Mary Elizabeth Moss
金额：
$ 5.05万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-10 至 2021-06-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908157
关键词：
Actins Adhesions Aldosterone American Animals Arterial Fatty Streak Arteries Atherosclerosis Autoimmune Diseases Automobile Driving Binding Blood Vessels Cardiovascular Diseases Cardiovascular system Caring Cause of Death Cell Culture Techniques Cells Cholesterol Chronic Clinical Clinical Research Collaborations Cultured Cells Dangerousness Data Development Dyslipidemias Endothelial Cells Endothelium Event Extravasation Fibrosis Flow Cytometry Foundations Functional disorder Health Heart failure High Fat Diet Histologic Human Hyperlipidemia Hypertension Immunology In Vitro Infiltration Inflammation Inflammatory Infusion procedures Intercellular Junctions Investigation Ischemic Stroke Knock-out Lead Leukocytes Light Lipids Measures Mediating Methods Mineralocorticoid Receptor Mitogen-Activated Protein Kinases Modeling Morbidity - disease rate Morphology Mus Myocardial Infarction Necrosis Neoplasm Metastasis Obesity Oxides Pathology Pathway interactions Permeability Phenotype Phospholipids Physicians Plant Roots Plasma Proteins Prevention Process Publishing Randomized Clinical Trials Receptor Activation Receptor Cell Receptor Inhibition Research Risk Risk Factors Role Rupture Scientist Signal Pathway Signal Transduction Stress Fibers Stroke T-Lymphocyte Testing Thrombosis Training Vascular Diseases Vascular Endothelial Cell Veins Viral Vector Work adeno-associated viral vector aortic arch atherogenesis atherosclerotic plaque rupture cadherin 5 cardiovascular risk factor career clinically significant endothelial dysfunction in vivo intravital microscopy junctional adhesion molecule limb ischemia macrophage meetings migration monolayer mortality mouse model mutant novel novel therapeutics occludin overexpression prevent recruit response src-Family Kinases training opportunity vascular inflammation

项目摘要

Project Summary/Abstract Cardiovascular disease is the most common cause of death in the USA, mainly due to rupture of atherosclerotic plaques causing myocardial infarction (MI) and stroke. Excess activation of the mineralocorticoid receptor (MR) is associated with vascular inflammation, atherosclerotic plaque rupture, and increased risk of MI and stroke. As MR activation is associated with obesity, heart failure, and hypertension, all very common health conditions, the majority of Americans may be at increased risk for MI and stroke due to inappropriate MR activation. Prior research in our lab and others indicates that MR in the vasculature promotes vascular inflammation and atherosclerosis, while its inhibition results in smaller plaques and fewer adverse cardiovascular events in randomized clinical trials. In response to traditional cardiovascular risk factors such as hypertension, obesity, and, we have recently found, hyperlipidemia, the MR specifically within endothelial cells (EC-MR) mediates vascular dysfunction, which is widely known to be an early step in the formation of atherosclerotic plaques. We have also found that EC-MR promotes leukocyte adhesion and trans-endothelial migration, suggesting a mechanism for how the MR promotes vascular inflammation. We therefore hypothesize that hyperlipidemia induces EC-MR to maladaptively activate intracellular pathways that promote endothelial permeability, thereby facilitating leukocyte trans-endothelial migration and vascular inflammation and contributing to development of atherosclerotic plaques with a phenotype that is prone to rupture. To investigate this hypothesis, we have developed a novel mouse model with the MR specifically deleted from endothelial cells, which we inject with a viral vector containing constitutively active PCSK9 to induce hyperlipidemia and atherosclerosis. In aim 1 of this proposal, we will investigate the role of EC-MR in plaque formation and morphology, vascular inflammation, and leukocyte trans-endothelial migration in vivo using this mouse model. In aim 2, we will treat isolated endothelial cells in culture with oxidized phospholipids to model atherogenic conditions and investigate intracellular signaling, cell-cell junction stability, and leukocyte trans- endothelial migration in vitro. Successful completion of our aims will result in substantial advances in our understanding of atherosclerosis and inflammation and could lead to novel therapies specifically targeting EC- MR to reduce atherosclerotic plaque burden and plaque rupture, drastically reducing the morbidity and mortality from cardiovascular disease. This proposal also includes a detailed training plan including coursework, collaborations, presentations at national meetings, and integration of clinical training to prepare the PI for a successful career as a physician-scientist.

项目摘要/摘要心血管疾病是美国最常见的死亡原因，主要是由于引起心肌梗塞（MI）和中风的动脉粥样硬化斑块。过量激活矿物皮质激素受体（MR）与血管炎症，动脉粥样硬化斑块破裂和增加了MI和中风的风险。由于MR激活与肥胖，心力衰竭和高血压有关非常常见的健康状况，大多数美国人可能会增加因MI和中风的风险增加不适当的MR激活。我们实验室的事先研究表明，脉管系统中的MR会促进血管炎症和动脉粥样硬化，而其抑制作用会导致斑块较小，不良不良随机临床试验中的心血管事件。响应传统的心血管危险因素，例如高血压，肥胖，我们最近发现，高脂血症，MR是内皮细胞内的（EC-MR）介导血管功能障碍，这是形成的早期一步动脉粥样硬化斑块。我们还发现EC-MR促进白细胞粘附和跨内皮迁移，暗示了MR如何促进血管炎症的机制。因此，我们假设高脂血症诱导EC-MR导致不良运动激活细胞内途径内皮渗透性，从而促进白细胞跨内皮迁移和血管炎症并促进具有容易破裂的表型的动脉粥样硬化斑块的发展。到研究了这一假设，我们开发了一种新型的小鼠模型，MR专门从中删除内皮细胞，我们将其注入含有组成型活性PCSK9的病毒载体以诱导高脂血症和动脉粥样硬化。在该提案的目标1中，我们将研究EC-MR在斑块中的作用形成和形态，血管炎症和白细胞在体内迁移的白细胞迁移鼠标模型。在AIM 2中，我们将用氧化的磷脂在培养中处理分离的内皮细胞以建模动脉粥样硬化条件并研究细胞内信号传导，细胞 - 细胞连接稳定性和白细胞反式体外内皮迁移。成功完成我们的目标将在我们的了解动脉粥样硬化和炎症，并可能导致新的疗法专门针对EC- MR减轻动脉粥样硬化斑块负担和斑块破裂，大大降低了发病率和心血管疾病的死亡率。该建议还包括一个详细的培训计划课程工作，合作，在全国会议上的演讲以及临床培训的整合以准备作为医生科学家成功职业生涯的PI。