Apolipoprotein C3-loading of apolipoprotein B100 lipoproteins and cardiovascular disease in patients with type 1 diabetes

载脂蛋白 B100 脂蛋白的载脂蛋白 C3 负载与 1 型糖尿病患者的心血管疾病

• 批准号: 10370044
• 负责人: JAY W HEINECKE
• 金额: $ 86.23万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-05 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370044
• 关键词: Address; Age; Antisense Oligonucleotide Therapy; Antisense Oligonucleotides; Apolipoproteins; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Blood; Blood Pressure; Body fat; Body mass index; Cardiovascular Diseases; Cardiovascular system; Clinical Research; Clinical Trials; Collaborations; Complement; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Coronary artery; Data; Diabetes Mellitus; Diabetic mouse; Endothelial Cells; Epidemiology; Glucose; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hyperglycemia; Hypertriglyceridemia; IDL lipoproteins; Impairment; Incidence; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Isotopes; LDL Cholesterol Lipoproteins; Lesion; Lipids; Lipolysis; Lipoproteins; Liver; Low-Density Lipoproteins; Metabolic; Metabolic Clearance Rate; Methods; Mus; Myeloid Cells; Normal Range; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Plasma; Production; Prospective Studies; Proteins; Proteomics; Research Design; Risk; Risk Factors; Sampling; Series; Serum; Smooth Muscle Myocytes; Study Subject; Testing; Triglycerides; Universities; Very low density lipoprotein; Washington; Work; base; cardiovascular disorder prevention; cardiovascular disorder risk; coronary artery calcium; diabetic; experimental study; follow-up; glycemic control; high risk; insight; ion mobility; low density lipoprotein triglyceride; metabolic abnormality assessment; mouse model; non-diabetic; novel strategies; particle; premature; prevent; prospective; risk prediction; sex; stable isotope; therapeutic target

We recently showed that serum levels of apolipoprotein C3 (APOC3) predicted incident cardiovascular disease (CVD) in CACTI, a prospective study of subjects with type 1 diabetes mellitus (T1DM). In complementary mechanistic studies, we found that reducing APOC3 levels with an antisense oligonucleotide (ASO) prevented lesion progression in a mouse model of T1DM and that apolipoprotein B (APOB)-containing lipoproteins were driving accelerated diabetic atherosclerosis. These observations are important because they strongly support the proposal that APOC3 promotes atherosclerosis in the setting of T1DM in both humans and mice. This is particularly important because ASOs to APOC3 are under investigation in humans, raising the possibility that it may be possible to reduce CVD risk in T1DM patients by lowering APOC3 levels. Our preliminary data strongly support the hypothesis that APOC3 accumulation in APOB100-containing lipoproteins, intermediate-density lipoprotein (IDL) and LDL, makes these particles atherogenic in T1DM. To test this hypothesis, and to lay the groundwork for a clinical trial of APOC3 ASO therapy in the prevention of CVD in T1DM patients, we propose two specific aims. First, we will determine whether levels of APOC3 in IDL and/or LDL predict incident CVD risk in the Pittsburgh Epidemiology of Diabetes Complications study, a large prospective study. Our proposed study is well powered with ~550 T1DM patients and >30% rate of incident CVD. These studies will take advantage of a state-of-the-art method we developedtermed calibrated ion mobility analysisthat quantifies molar concentrations of APOB100-containing lipoprotein particles in blood. Our primary analysis will be to determine if i) IDL-APOC3 and/or ii) LDL-APOC3 predict incident CVD. Second, we will perform detailed metabolic studies to determine how T1DM alters hepatic APOC3 production and VLDL turnover rates, and how this impacts the accumulation of APOC3 in LDL and IDL in humans with and without T1DM. Based on our mouse studies, we hypothesize that T1DM promotes increased levels of hepatic APOC3 production that impairs TG lipolysis, resulting in increased levels of IDL-APOC3 and/or LDL-APOC3. We will complement these analyses with comprehensive analyses of the metabolic factors (e.g., body fat composition, liver triglycerides, hepatic sinusoidal insulin concentration) that might regulate the concentration of APOC3 in LDL, IDL and VLDL. Identifying patients at increased risk for CVD should provide mechanistic insights into the pathogenesis of accelerated atherosclerosis in T1DM. Moreover, it would lay the groundwork for a clinical study of APOC3 lowering therapy in T1DM because it could target patients at high risk of CVD.

我们最近发现血清载脂蛋白C3（APOC 3）水平可预测心血管疾病的发生 (CVD)在CACTI中，1型糖尿病（T1 DM）受试者的前瞻性研究。以互补 机制研究中，我们发现用反义寡核苷酸（阿索）降低APOC 3水平可以防止 在T1 DM小鼠模型中病变进展和含载脂蛋白B（APOB）的脂蛋白被 加速糖尿病动脉粥样硬化这些观察结果很重要，因为它们强烈支持 APOC 3在人类和小鼠的T1 DM背景下促进动脉粥样硬化的提议。这是 特别重要的是，因为APOC 3的ASO正在人类中进行研究，这增加了它的可能性。 可能通过降低APOC 3水平来降低T1 DM患者的CVD风险。 我们的初步数据强烈支持这一假设，即APOC 3在含有APOB 100的细胞中的积累， 脂蛋白、中密度脂蛋白（IDL）和LDL使这些颗粒在T1 DM中致动脉粥样硬化。到 为了验证这一假设，并为APOC 3阿索治疗预防糖尿病的临床试验奠定基础， 对于T1 DM患者的CVD，我们提出了两个具体目标。 首先，我们将确定IDL和/或LDL中的APOC 3水平是否可以预测心血管事件的风险。 匹兹堡糖尿病并发症流行病学研究，大型前瞻性研究。我们建议的研究是 把握度良好，约550例T1 DM患者和>30%的CVD事件发生率。这些研究将利用一个 我们开发了一种称为校准离子迁移率分析的最先进的方法， 血液中含有APOB 100的脂蛋白颗粒的浓度。我们的主要分析将是确定 如果i）IDL-APOC 3和/或ii）LDL-APOC 3预测发生CVD。 其次，我们将进行详细的代谢研究，以确定T1 DM如何改变肝脏APOC 3 生产和VLDL周转率，以及这如何影响LDL和IDL中APOC 3的积累， 患有和不患有T1 DM的人。基于我们的小鼠研究，我们假设T1 DM促进增加 肝脏APOC 3产生水平降低，损害TG脂解，导致IDL-APOC 3水平升高 和/或LDL-APOC 3。我们将通过对代谢因素的综合分析来补充这些分析 (e.g.,体脂肪组成、肝甘油三酯、肝窦胰岛素浓度），可能调节 LDL、IDL和VLDL中的APOC 3浓度。 识别CVD风险增加的患者应该为CVD的发病机制提供机制性见解。 加速T1 DM的动脉粥样硬化。此外，这将为APOC 3的临床研究奠定基础 降低T1 DM的治疗水平，因为它可以针对心血管疾病高风险的患者。