Nitro-Fatty Acids and Cardiovascular Disease

硝基脂肪酸与心血管疾病

基本信息

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
项目类别：
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

项目摘要

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.

动脉粥样硬化是造成心血管疾病的主要原因，也是全球死亡的主要原因。糖尿病患病率在全球上升，心血管疾病（CVD）是死亡率的主要原因在糖尿病患者中。最小化CVD的风险是糖尿病治疗的关键临床目标患者。反过来，高晶状体诱导了细胞水平的血管组织中的大量改变加速了动脉粥样硬化过程。实际上，长期暴露于高血糖被认为是与糖尿病有关的动脉粥样硬化发病机理的主要因素。内皮细胞（EC）功能障碍是动脉粥样硬化的标志和初步步骤，并在糖尿病中加剧。尽管如此，可用的治疗方法针对与糖尿病有关的动脉粥样硬化。转录因子-EB（TFEB），a 溶酶体生物发生和自噬的关键调节剂对各种疾病具有有益作用。我们的解决EC中TFEB功能的系统研究发现TFEB促进自噬并抑制体外氧化应激和炎症。在CVD模型中，我们证明了在EC特异性TFEB中转基因促进缺血后血管生成，并在层流中起动脉保护作用。 tfeb 抑制内皮炎症，导致体内动脉粥样硬化减少。我们最近报道了EC- TFEB调节血浆葡萄糖。我们的初步研究表明GPNMB可能是一种新颖的转录 TFEB介导其下游效应的目标。总的来说，这些数据表明TFEB激活可能同时与糖尿病相关的改善动脉粥样硬化。共轭亚油酸（CLA）是人类脂肪酸硝化的优先底物。口服后胃CLA硝化 CLA和无机亚硝酸盐（NO2）在人和小鼠的纳摩尔范围内呈现NO2-CLA，使其成为 CVD有吸引力的干预。我们的初步数据表明，NO2-CLA在TFEB-中调节自噬依赖方式并增强EC中的TFEB转录活性。根据这些证据，我们将测试 NO2-CLA直接激活内皮TFEB的中心假设可防止动脉粥样硬化通过GPNMB与糖尿病有关。通过在体外和体内获得功能丧失策略，使用专门为这些研究和NO2-CLA治疗的独特动物模型，我们将解决两个全面的特定目标。在AIM 1中，我们将证明NO2-CLA可以增强TFEB依赖性通过GPNMB在体外保护作用，并专注于潜在机制，同时显示了 TFEB Cys212，TFEB中潜在的直接S-硝基烷基化位点。在AIM 2中，我们将确定NO2-CLA抑制在体内糖尿病性动脉粥样硬化模型中通过TFEB和GPNMB通过TFEB和GPNMB的动脉粥样硬化。通过建立口服NO2-CLA作为通过TFEB和GPNMB运营的可行的新治疗策略研究可能会加速这些发现为临床前试验以治疗动脉粥样硬化在糖尿病患者中，有助于改变当前的临床范例来治疗代谢疾病。