Role of Adiposomes in Diabetes-Associated Endothelial Dysfunction and Restorative Effects of Exercise and Metabolic Surgery

脂肪体在糖尿病相关内皮功能障碍中的作用以及运动和代谢手术的恢复作用

• 批准号: 10532237
• 负责人: Abeer M Mohamed
• 金额: $ 74.39万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532237
• 关键词: Adipocytes; Adipose tissue; Adult; Aerobic Exercise; Affect; Biological; Biopsy; Blood Vessels; Body Weight decreased; Cardiovascular Diseases; Caveolae; Cell membrane; Cell surface; Cells; Ceramides; Characteristics; Chemicals; Communication; Cytoprotection; Data; Development; Diabetes Mellitus; Endothelial Cells; Endothelium; Event; Exercise; Glucose; Glycosphingolipids; Goals; Homeostasis; Human; Hyperglycemia; Hypoxia; In Vitro; Individual; Inflammation; Insulin Resistance; Lipids; Measures; Mediating; Mediator; Membrane; Metabolic; MicroRNAs; Molecular; NOS3 gene; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Permeability; Phosphorylation; Physical activity; Predisposing Factor; Process; Production; Property; Proteins; Randomized; Research; Risk; Role; Sampling; Signal Transduction; Structure; Surface; Testing; Therapeutic; Therapeutic Intervention; Thinness; Tissues; Vascular Diseases; Visceral; angiogenesis; arteriole; atherogenesis; bariatric surgery; cardiovascular risk factor; comorbidity; diabetic; effectiveness testing; endothelial dysfunction; exercise training; extracellular vesicles; glycosylation; improved; intercellular communication; lipid metabolism; mimetics; new therapeutic target; preconditioning; prevent; sensor; shear stress; social; src-Family Kinases; subcutaneous; synergism; transcytosis; uptake; vascular endothelial dysfunction; weight loss intervention

ABSTRACT The development of type II diabetes (T2D) is strongly associated with obesity, and both are well-established risk factors for cardiovascular disease. Vascular dysfunction is an early event in developing cardiovascular disease in obese diabetic (OB-T2D) patients. Therefore, we set our long-term goal to define molecular mechanisms of vascular dysfunction and corrective strategies that target these mechanisms, such as physical activity and weight loss. We recently discovered that human adipose tissues release extracellular vesicles (adiposomes) that are efficiently captured by endothelial cells. Adiposomes are known to carry bioactive cargos such as proteins and micro RNAs; however, their lipid content has not been studied, neither their ability to transfer their lipid cargo to endothelial cells. In the current application, we propose investigating the role of adiposomes in communicating the unhealthy milieu, mainly dysregulated lipids, to endothelial cells in OB-T2D subjects. On top of these lipid species that we propose to be carried by adiposomes are glycosphingolipids (GSLs). GSLs originate from ceramide glycosylation, a chemical process that is upregulated in the presence of inflammation and high glucose levels. Our preliminary findings showed that in endothelial cells, GSL-rich adiposomes disturb plasma membrane structure and subsequently induces endothelial dysfunction. Moreover, we found preconditioning endothelial cells with high shear stress (which is an exercise mimetic) protected endothelial cells from the detrimental effects caused by adiposomes. Therefore, our central hypothesis is that adipose tissues in OB-T2D patients release GSL-loaded adiposomes that induce vascular endothelial dysfunction. We propose that exercise and weight loss interventions (bariatric surgery) will restore adipose tissue homeostasis, reduce GSL-loaded adiposomes, and subsequently alleviate vascular risk in OB-T2D patients. We will test our hypotheses by pursuing the following Aims: Aim 1: Investigate the role of GSL-rich adiposomes in the pathogenesis of endothelial dysfunction in OB- T2D adults; Aim 2: Test the effectiveness of exercise training in reducing adiposome-mediated effects on vascular function; and Aim 3: Examine changes in adiposome/caveolae axis following metabolic surgery and their association with vascular function. This study will improve our mechanistic understanding of the biological underpinning of adiposome production, packaging, and role in inducing ED under conditions of obesity and T2D. It will also identify adiposomes and the proposed mechanisms of their interaction with endothelial cells as novel therapeutic targets for improving vascular function in OB-T2D individuals. Once these pathways are elucidated, strategies for targeting them can be advanced, leading to an improved therapeutic management of T2D-related cardiovascular disease.

抽象的 II 型糖尿病 (T2D) 的发展与肥胖密切相关，两者都是公认的风险 心血管疾病的因素。血管功能障碍是发生心血管疾病的早期事件 肥胖糖尿病（OB-T2D）患者。因此，我们设定了长期目标来定义分子机制 血管功能障碍和针对这些机制的纠正策略，例如体力活动和体重 损失。我们最近发现人类脂肪组织释放细胞外囊泡（脂肪体）， 被内皮细胞有效捕获。已知脂肪体携带生物活性物质，例如蛋白质和 微小RNA；然而，它们的脂质含量尚未研究，也没有研究它们将脂质货物转移到 内皮细胞。在当前的应用中，我们建议研究脂肪体在沟通中的作用 OB-T2D 受试者的内皮细胞不健康的环境，主要是脂质失调。在这些脂质之上 我们建议脂肪体携带的种类是鞘糖脂（GSL）。 GSL 源自 神经酰胺糖基化，一种在炎症和高葡萄糖存在下上调的化学过程 水平。我们的初步研究结果表明，在内皮细胞中，富含 GSL 的脂肪体会干扰质膜 结构并随后诱导内皮功能障碍。此外，我们发现预处理内皮细胞 具有高剪切应力（模拟运动）的细胞可以保护内皮细胞免受有害影响 由脂肪体引起。因此，我们的中心假设是 OB-T2D 患者的脂肪组织释放 负载 GSL 的脂肪体可诱导血管内皮功能障碍。我们建议运动和减肥 干预措施（减肥手术）将恢复脂肪组织稳态，减少 GSL 负载的脂肪体，以及 随后减轻 OB-T2D 患者的血管风险。我们将通过以下方式检验我们的假设 目的： 目标 1：研究富含 GSL 的脂肪体在 OB- 内皮功能障碍发病机制中的作用 T2D 成人；目标 2：测试运动训练在减少脂肪体介导的影响方面的有效性 血管功能；目标 3：检查代谢手术后脂肪体/凹陷轴的变化 它们与血管功能的关系。这项研究将提高我们对生物机制的理解 脂肪体产生、包装的基础，以及在肥胖和 T2D 条件下诱导 ED 的作用。 它还将鉴定脂肪体及其与内皮细胞相互作用的新机制。 改善 OB-T2D 个体血管功能的治疗目标。一旦这些途径被阐明， 可以改进针对它们的策略，从而改善 T2D 相关的治疗管理 心血管疾病。