Nitro-Fatty Acids and Cardiovascular Disease

硝基脂肪酸与心血管疾病

• 批准号: 10670429
• 负责人: YUQING Eugene CHEN
• 金额: $ 72.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670429
• 关键词: Acceleration; Accounting; Address; Adult; Adverse effects; Animal Model; Animals; Anti-Inflammatory Agents; Antidiabetic Drugs; Aorta; Atherosclerosis; Autophagocytosis; Biogenesis; Blood Vessels; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular Models; Cause of Death; Cell Separation; Cells; Cessation of life; Child; Clinical; Clinical Treatment; Conjugated Linoleic Acids; Coronary artery; Data; Dependence; Development; Diabetes Mellitus; Diet; Disease; Disease Outcome; Endothelial Cells; Endothelium; Exposure to; Fatty Acids; Functional disorder; Genes; Genetic Engineering; Genetic Transcription; Glucose; Glycoproteins; Goals; Homeostasis; Human; Hyperglycemia; Hypertriglyceridemia; Hypoglycemic Agents; In Vitro; Inflammation; Inflammatory; Intervention; Ischemia; Knock-out; Knockout Mice; Mediating; Mediator; Metabolic Diseases; Modeling; Mus; Myocardial Infarction; Neurodegenerative Disorders; Nitric Oxide; Nitrites; Nitrogen Dioxide; Nonmetastatic; Nuclear Translocation; Obesity; Oleic Acids; Oral; Oxidative Stress; Pathogenesis; Pathology; Patients; Peripheral Vascular Diseases; Persons; Pharmaceutical Preparations; Phase II Clinical Trials; Plasma; Play; Population; Prediabetes syndrome; Prevalence; Process; Production; Property; Publishing; Regulation; Reporting; Research; Residual state; Risk; Role; Site; Stimulus; Stomach; Stroke; Technology; Testing; Therapeutic; Tissues; Transgenes; Transgenic Organisms; Translations; Work; angiogenesis; atheroprotective; atherosclerosis risk; cardiovascular disorder risk; cardiovascular disorder therapy; diabetes management; diabetic; diabetic patient; diabetogenic; diet-induced obesity; dietary; dietary supplements; functional restoration; gain of function; glucose tolerance; glycoprotein NMB; improved; in vivo; in vivo Model; insulin sensitivity; loss of function; melanoma; mortality; mouse model; nanomolar; nitrated conjugated linoleic acid; nitration; novel; novel therapeutic intervention; pharmacologic; preclinical trial; prevent; protective effect; protein B; prototype; risk minimization; transcription factor; transcriptome sequencing

Atherosclerosis is the primary cause of cardiovascular diseases and a leading cause of death worldwide. Diabetes prevalence is on the rise globally, with cardiovascular diseases (CVD) as the main cause of mortality among diabetic patients. Minimizing the risk of CVD is a critical clinical goal in the management of diabetic patients. In turn, hyperglicemia induces a large number of alterations in the vascular tissue at the cellular level that accelerate the atherosclerotic process. In fact, prolonged exposure to hyperglycemia is recognized as a major factor in the pathogenesis of atherosclerosis associated with diabetes. Endothelial cell (EC) dysfunction is a hallmark and initial step of atherosclerosis and is aggravated in diabetes. Nonetheless, there is a paucity in available treatments to target atherosclerosis associated with diabetes. Transcription factor-EB (TFEB), a crucial regulator of lysosomal biogenesis and autophagy, has beneficial effects in various diseases. Our systematic studies to address TFEB function in ECs uncovered that TFEB promotes autophagy and inhibits oxidative stress and inflammation in vitro. In models of CVD, we demonstrated that in EC-specific TFEB transgene promotes post-ischemic angiogenesis and plays an atheroprotective role in laminar flow. TFEB inhibits endothelial inflammation resulting in reduced atherosclerosis in vivo. We recently reported that EC- TFEB regulates plasma glucose. Our preliminary studies indicate that GPNMB may be a novel transcriptional target of TFEB mediating its downstream effects. Collectively, these data suggest that TFEB activation might contribute to ameliorate atherosclerosis in association with diabetes concurrently. Conjugated linoleic acid (CLA) is the preferential substrate for fatty acid nitration in humans. Gastric CLA nitration upon oral delivery of CLA and inorganic nitrite (NO2) renders NO2-CLA in the nanomolar range in humans and mice, making it an attractive intervention for CVD. Our preliminary data reveal that NO2-CLA regulates autophagy in a TFEB- dependent manner and enhances TFEB transcriptional activity in ECs. Based on these evidences, we will test the central hypothesis that direct activation of endothelial TFEB by NO2-CLA protects against atherosclerosis associated with diabetes through GPNMB. Through gain- and loss-of-function strategies in vitro and in vivo, using unique animal models generated specifically for these studies and NO2-CLA treatment, we will address two comprehensive specific aims. In Aim 1, we will demonstrate that NO2-CLA enhances TFEB-dependent protective effects in vitro via GPNMB and focus on the underlying mechanism, while showing the critical role of TFEB Cys212, a potential direct S-nitroalkylation site in TFEB. In Aim 2, we will establish that NO2-CLA inhibits atherosclerosis through TFEB and GPNMB in a diabetogenic atherosclerosis model in vivo. By establishing oral delivery of NO2-CLA as a feasible new therapeutic strategy operating through TFEB and GPNMB, this study will likely accelerate translation of these findings into preclinical trials for the treatment of atherosclerosis in diabetic patients, contributing to change current clinical paradigms for the treatment of metabolic diseases.

动脉粥样硬化是心血管疾病的主要原因，也是世界范围内的主要死亡原因。 糖尿病的患病率在全球范围内呈上升趋势，心血管疾病（CVD）是导致死亡的主要原因 在糖尿病患者中。最大限度地降低心血管疾病的风险是糖尿病管理的关键临床目标。 患者反过来，高血糖症在细胞水平上诱导血管组织的大量改变 加速动脉粥样硬化的过程事实上，长期暴露于高血糖被认为是一种 糖尿病相关动脉粥样硬化发病机制中的主要因素。内皮细胞（EC）功能障碍 是动脉粥样硬化的标志和初始步骤，并且在糖尿病中加重。然而，在这方面， 针对糖尿病相关动脉粥样硬化的现有治疗方法。转录因子-EB（TFEB），a 溶酶体生物发生和自噬的重要调节剂，在各种疾病中具有有益作用。我们 针对TFEB在EC中功能的系统研究发现，TFEB促进自噬并抑制自噬， 体外氧化应激和炎症。在CVD模型中，我们证明了EC特异性TFEB 转基因促进缺血后血管生成，并在层流中发挥动脉粥样硬化保护作用。TFEB 抑制内皮炎症，导致体内动脉粥样硬化减少。我们最近报道说，EC- TFEB调节血糖。我们的初步研究表明GPNMB可能是一种新的转录因子， TFEB介导其下游效应的靶点。总的来说，这些数据表明TFEB激活可能 有助于同时改善与糖尿病相关的动脉粥样硬化。共轭亚油酸 (CLA)是人体脂肪酸硝化的优先底物。经口给药后的胃CLA硝化 CLA和无机亚硝酸盐（NO2）使NO2-CLA在人类和小鼠中处于纳摩尔范围内，使其成为一种 对CVD有吸引力的干预。我们的初步数据表明，NO2-CLA调节TFEB中的自噬， 依赖的方式，并增强内皮细胞中TFEB的转录活性。根据这些证据，我们将测试 核心假设是NO2-CLA直接激活内皮TFEB可以预防动脉粥样硬化 通过GPNMB与糖尿病相关。通过体外和体内的功能获得和丧失策略， 使用专门为这些研究和NO2-CLA治疗产生的独特动物模型，我们将解决 两个具体目标。在目的1中，我们将证明NO2-CLA增强TFEB依赖性的 通过GPNMB在体外的保护作用，并侧重于潜在的机制，同时显示了关键作用， TFEB Cys 212，TFEB中潜在的直接S-硝基烷基化位点。在目标2中，我们将确定NO2-CLA抑制 在体内糖尿病致动脉粥样硬化模型中通过TFEB和GPNMB的动脉粥样硬化。通过建立 口服NO2-CLA作为一种可行的新的治疗策略，通过TFEB和GPNMB操作，这 这项研究可能会加速将这些发现转化为动脉粥样硬化治疗的临床前试验 在糖尿病患者中，有助于改变目前治疗代谢性疾病的临床范例。