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(由申请人提供)：糖尿病的心血管并发症部分源于内皮细胞(ECs)、巨噬细胞和血管平滑肌细胞(VSMCs)功能的前动脉粥样硬化改变。因此，糖尿病引起的VSMCs中miRNA表达的改变可能通过外切体介导的miRNA转移促进血管内皮细胞活化和动脉炎症，从而促进糖尿病心血管并发症的发生。这项建议的目的是确定外切体介导的miR-221/222转移在糖尿病介导的心血管疾病增加中的影响。我们的初步数据表明，糖尿病VSMC来源的外切体(DVEs)促进内皮细胞激活、内皮功能障碍和巨噬细胞向炎症表型的转变。此外，我们还发现，在体内，DVE促进动脉粥样硬化斑块的形成。这一建议假设：糖尿病伴随着VSMCs分泌的外体miR-221/222增加，通过促进内皮细胞激活和功能障碍加速心血管疾病的进展，以及巨噬细胞向促炎表型(M1)的极化。这一假说将通过三个特定的目标来验证：1)证明DVE通过增加miR-221/222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的M1状态转变而促进内皮细胞激活和增加活性氧；3)DVE治疗后VSMCs中IGFR的丢失与DVE增加的miR-221/222含量和动脉粥样硬化斑块形成增加有关。目的1证明DVE促进动脉粥样硬化斑块的形成。AIMS 2将描述DVE如何促进EC功能障碍、EC激活和巨噬细胞向炎症表型的极化。每个目标还将研究miR-221/222在这些效应中的作用。目标3将扩展我们目前的研究结果，以了解DVE中miR-221/222增加的机制。总而言之，该项目的预期结果是一个证明，糖尿病伴随着血管内皮细胞和巨噬细胞中促进心血管疾病的DVEs的产生。这些数据将产生重大的积极影响，因为它们将确定糖尿病人群心血管疾病增加背后的新机制。这一建议中的研究是创新的，因为它将推动我们理解的范式转变 通过引入VSMCs改变EC和巨噬细胞功能的新机制，研究VSMCs在动脉粥样硬化病变形成中的作用。