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

项目摘要/摘要 心血管疾病是美国最常见的死亡原因，主要是由于心脏破裂 导致心肌梗塞(MI)和中风的动脉粥样硬化斑块。过度激活 盐皮质激素受体(MR)与血管炎症、动脉粥样硬化斑块破裂以及 增加心肌梗塞和中风的风险。由于MR激活与肥胖、心力衰竭和高血压有关，所有这些 非常常见的健康状况，大多数美国人可能因以下原因而增加患MI和中风的风险 不适当的MR激活。我们实验室和其他实验室的先前研究表明，血管系统中的MR促进 血管炎症和动脉粥样硬化，而它的抑制导致斑块变小，不良反应减少 随机临床试验中的心血管事件。应对传统的心血管危险因素，如 高血压、肥胖症，以及我们最近发现的高脂血症，尤其是内皮细胞内的MR (EC-MR)介导血管功能障碍，众所周知，这是高血压形成的早期步骤。 动脉粥样硬化斑块。我们还发现EC-MR促进白细胞黏附和跨内皮细胞 迁移，提示了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不适应性地激活促进 内皮通透性，从而促进白细胞跨内皮细胞迁移和血管炎症 并促进动脉粥样硬化斑块的发展，其表型容易破裂。至 为了研究这一假设，我们开发了一种新的小鼠模型，其中MR特别是从 内皮细胞，我们注射含有结构性活性PCSK9的病毒载体来诱导 高脂血症和动脉粥样硬化。在本提案的目标1中，我们将研究EC-MR在斑块中的作用 体内的形成和形态、血管炎症和白细胞跨内皮细胞迁移 老鼠模型。在目标2中，我们将在培养中用氧化磷脂处理分离的内皮细胞，以建立 并研究细胞内信号转导、细胞-细胞连接稳定性和白细胞转运。 血管内皮细胞在体外迁移。成功完成我们的目标将导致我们的 了解动脉粥样硬化和炎症，并可能导致针对EC的新疗法- MR减少动脉粥样硬化斑块负担和斑块破裂，大大降低发病率和 心血管疾病的死亡率。该提案还包括一项详细的培训计划，包括 课程作业、协作、在国家会议上的陈述，以及整合临床培训以准备 作为一名内科科学家的成功职业生涯的PI。

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.