Role of VSMC-Derived Exosomes in the Cardiovascular Complications of Diabetes

VSMC 衍生的外泌体在糖尿病心血管并发症中的作用

• 批准号: 9251878
• 负责人: Thomas Cooper Woods
• 金额: $ 37.74万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251878
• 关键词: Adopted; American; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Automobile Driving; Blood Glucose; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion Molecules; Cell surface; Cells; Chronic Kidney Failure; Comorbidity; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diagnosis; Disease Progression; Endothelial Cells; Functional disorder; Generations; Genetic Transcription; Goals; Grant; Hyperplasia; Inflammation; Inflammatory; Insulin-Like Growth Factor Receptor; Laboratories; Leukocytes; Link; Mediating; Methodology; Methods; MicroRNAs; Molecular; Muscle Cells; Myocardial Infarction; NOS3 gene; Nitric Oxide; Outcome; Paracrine Communication; Phenotype; Population; Prevention; Production; Reactive Oxygen Species; Recruitment Activity; Research; Risk; Role; Site; Source; Stroke; Testing; Time; Vascular Smooth Muscle; Work; cofactor; diabetic; endothelial dysfunction; exosome; in vivo; innovation; macrophage; novel; prevent; public health relevance; response; vascular inflammation; vascular smooth muscle cell proliferation

 DESCRIPTION (provided by applicant): The cardiovascular complications of diabetes derive, in part, from pro-atherosclerotic changes in the function of endothelial cells (ECs), macrophages, and vascular smooth muscle cells (VSMCs). Thus, changes in miRNA expression in VSMCs as a result of diabetes may promote the cardiovascular complications of diabetes via exosome mediated transfer of miRNA that induce endothelial activation and arterial inflammation. The objective of this proposal is determining the impact of exosome mediated transfer of miR-221/222 in the diabetes mediated increase in cardiovascular disease. Our preliminary data demonstrate that diabetic VSMC-derived exosomes (DVEs) promote endothelial cell activation, endothelial dysfunction, and a shift of macrophages toward an inflammatory phenotype. Furthermore, we found that DVEs promote atherosclerotic plaque formation in vivo. This proposal hypothesizes: Diabetes is accompanied by increased miR-221/222 in the exosomes secreted by VSMCs that accelerates cardiovascular disease progression by promoting endothelial cell activation and dysfunction as well as a polarization of macrophages toward a pro-inflammatory phenotype (M1). The hypothesis will be tested through three specific aims: 1) Demonstrate that DVEs promote atherosclerotic plaque formation through an increase in miR-221/222.; 2) Demonstrate that DVEs promote endothelial cell activation and increased reactive oxygen species through eNOS uncoupling as well as a shift in macrophage phenotype toward the pro-inflammatory M1 state; 3) Link loss of the IGFR in VSMCs to the increased miR-221/222 content of DVEs and increased atherosclerotic plaque formation in response to DVE treatment. Aim 1 will demonstrate that DVEs promote atherosclerotic plaque formation. Aims 2 will characterize how DVEs promote EC dysfunction, EC activation, and polarization of macrophages toward an inflammatory phenotype. Each aim will also examine the role of miR-221/222 in these effects. Aim 3 will extend the findings of our current research to understand the mechanism underlying the increase in miR-221/222 in DVEs. Together the expected outcome of this project is a demonstration that diabetes is accompanied by the generation of DVEs that promote cardiovascular disease in ECs and macrophages. These data will have a significant positive impact as they will identify novel mechanisms behind the increased cardiovascular disease in the diabetic population. The research in this proposal is innovative because it will drive a paradigm shift in our understanding of the role of VSMCs in atherosclerotic lesion formation by introducing a novel mechanism whereby VSMCs alter EC and macrophage function.

 描述（由适用提供）：糖尿病的心血管并发症部分源自内皮细胞（ECS），巨噬细胞和血管平滑肌细胞（VSMC）功能的促进性变化。这就是糖尿病导致的MiRNA表达的变化，可能会通过外泌体介导的miRNA转移而促进糖尿病的心血管并发症，从而诱导内皮激活和动脉炎症。该提案的目的是确定外泌体介导的miR-221/222在糖尿病中介导的心血管疾病增加的影响。我们的初步数据表明，糖尿病VSMC衍生的外泌体（DVE）促进内皮细胞激活，内皮功能障碍以及巨噬细胞向炎症表型的转移。此外，我们发现DVE促进了体内动脉粥样硬化斑块的形成。该提案假设：糖尿病伴随着由VSMC分泌的外泌体中的miR-221/222增加，这些外泌体通过促进内皮细胞的激活和功能障碍，以及巨噬细胞对巨噬细胞的极化促进心血管疾病的进展加速，并将巨噬细胞降至促造影感染现象（MM1）。该假设将通过三个特定目的进行检验：1）证明DVE通过MiR-221/222的增加来促进动脉粥样硬化斑块的形成。 2）证明DVE通过eNOS解偶联以及巨噬细胞表型向促炎性M1态的转移促进内皮细胞活化并增加活性氧。 3）VSMC中IGFR的链接损失与DVE的miR-221/222含量增加，并增加了动脉粥样硬化的斑块形成，以响应DVE处理。 AIM 1将证明DVE促进动脉粥样硬化斑块的形成。 AIMS 2将表征DVE如何促进EC功能障碍，EC激活以及巨噬细胞对炎症表型的极化。每个目标还将检查miR-221/222在这些影响中的作用。 AIM 3将扩展我们当前研究的发现，以了解DVE中miR-221/222增加的机制。该项目的预期结果共同证明了糖尿病是通过促进EC和巨噬细胞中心血管疾病的DVE来实现的。这些数据将产生重大的积极影响，因为它们将确定糖尿病种群中心血管疾病增加的新机制。该提案中的研究具有创新性，因为它将推动我们理解的范式转变 VSMC在动脉粥样硬化病变形成中的作用，通过引入一种新的机制，从而改变EC和巨噬细胞功能。