Project 1. Diabetes, triglyceride-rich lipoproteins, and advanced atherosclerosis

项目1. 糖尿病、富含甘油三酯的脂蛋白和晚期动脉粥样硬化

• 批准号: 10450861
• 负责人: Karin E. Bornfeldt
• 金额: $ 40.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450861
• 关键词: ANGPTL3 gene; Address; Affect; Antisense Oligonucleotides; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; CREB1 gene; Cardiovascular Diseases; Caspase; Cessation of life; Cholesterol; Complement; Cyclic AMP-Responsive DNA-Binding Protein; Data; Diabetes Mellitus; Diabetic mouse; Event; Exhibits; Health; Hemorrhage; Hepatic; Human; Human Genetics; Hypertriglyceridemia; Inflammasome; Insulin Receptor; Insulin Resistance; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; LDL Cholesterol Lipoproteins; Lesion; Lesion by Morphology; Link; Lipids; Lipoproteins; Mediating; Metabolic syndrome; Metabolism; Modeling; Mus; Mutation; Myeloid Cells; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Phenotype; Plasma; Prediabetes syndrome; Prevention strategy; Proteins; Publishing; Receptor Signaling; Residual state; Risk Factors; Role; Serum; Severities; Testing; Time; Triglyceride Metabolism; Triglycerides; atherosclerosis risk; cardiovascular disorder risk; diabetic; diabetic patient; in vivo; insight; interest; loss of function mutation; macrophage; mouse model; non-diabetic; novel; novel strategies; particle; prevent; trait; transcription factor; treatment effect; treatment strategy; uptake

Both type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS; also known as pre-diabetes) increase the risk of atherosclerosis, the leading cause of cardiovascular disease (CVD) events and death in diabetic patients. Even with statin treatment to effectively lower LDL cholesterol, diabetes is associated with increased CVD risk linked to abnormal metabolism of triglyceride-rich lipoproteins (TRLs) and their remnant lipoprotein particles (RLPs). Novel strategies to enhance TRL clearance have therefore recently generated significant interest, especially in the setting of diabetes. This application uses three strategies to increase TRL and RLP clearance in diabetes; i) inhibition of apolipoprotein C3 (APOC3), ii) inhibition of angiopoietin-like 3 (ANGPTL3), and iii) hepatic expression of an active form of the transcription factor CREB-H (cAMP response element-binding protein H). The proposed studies build on strong preliminary data demonstrating that diabetes accelerates progression of advanced lesions and that normalizing circulating levels of TRLs prevents atherosclerosis in diabetic mice. Furthermore, diabetes causes increased macrophage death associated with accumulation of cellular cholesterol and caspase 11 activation, which we hypothesize contributes to the more advanced atherosclerotic lesion phenotype. Collectively, our observations support the following hypothesis: Diabetes accelerates advanced atherosclerosis by increasing APOC3 and associated TRLs and RLPs, which in turn induce macrophage lipid loading and exacerbate the death of macrophages by pyroptosis. Such a mechanism could help explain the increased CVD risk in subjects with diabetes. The first specific aim will address whether APOC3-enriched TRLs/RLPs are required for diabetes- mediated atherosclerosis progression. We propose to test this hypothesis and to clarify the role of APOC3 by normalizing plasma APOC3 and/or TRL/RLP levels in mouse models of T1DM and MetS/T2DM by three distinct approaches; the use of an Apoc3 antisense oligonucleotide (ASO), an Angptl3 ASO, which reduces TRLs and other lipoproteins independent of hepatic Apoc3 expression, and hepatic expression of CREB-H, which lowers TRLs without affecting total plasma levels of APOC3. Contrasting the effects of these treatments will provide new insights into the role of APOC3 versus TRL/RLP lowering. The second specific aim will determine whether pyroptosis mediated by APOC3-enriched TRLs/RLPs contributes to lesional macrophage death and advanced lesions in diabetes. We propose to mechanistically test the importance of this pathway by using mice deficient in caspase 11 and gasdermin D, its downstream effector, in myeloid cells. We also expect that pyroptosis will be prevented by TRL-lowering in diabetic mice. The in vivo studies will be complemented by mechanistic studies in macrophages to clarify the pathways responsible in diabetes-induced macrophage death, and by studies addressing mechanisms whereby reduced insulin receptor signalling leads to increased levels of APOC3 in models of T1DM and MetS/T2DM.

1 型糖尿病 (T1DM)、2 型糖尿病 (T2DM) 和代谢综合征 (MetS)；还有 称为糖尿病前期）会增加动脉粥样硬化的风险，动脉粥样硬化是心血管疾病 (CVD) 的主要原因 糖尿病患者的事件和死亡。即使使用他汀类药物治疗可以有效降低低密度脂蛋白胆固醇、糖尿病 与富含甘油三酯的脂蛋白 (TRL) 代谢异常相关的 CVD 风险增加相关 及其残余脂蛋白颗粒（RLP）。因此，提高 TRL 清除率的新策略 最近引起了人们的极大兴趣，特别是在糖尿病方面。该应用程序使用三个 增加糖尿病患者 TRL 和 RLP 清除率的策略； i) 抑制载脂蛋白 C3 (APOC3)，ii) 抑制血管生成素样 3 (ANGPTL3)，以及 iii) 转录活性形式的肝脏表达 CREB-H 因子（cAMP 反应元件结合蛋白 H）。拟议的研究建立在强有力的初步基础上 数据表明，糖尿病会加速晚期病变的进展，并使循环正常化 TRL 水平可预防糖尿病小鼠的动脉粥样硬化。此外，糖尿病会导致巨噬细胞增加 死亡与细胞胆固醇积累和 caspase 11 激活相关，我们假设 有助于更先进的动脉粥样硬化病变表型。总的来说，我们的观察结果支持 以下假设：糖尿病通过增加 APOC3 和 相关的 TRL 和 RLP，进而诱导巨噬细胞脂质负荷并加剧巨噬细胞的死亡 巨噬细胞焦亡。这种机制可能有助于解释患有以下疾病的受试者心血管疾病风险增加的原因： 糖尿病。第一个具体目标将解决糖尿病是否需要富含 APOC3 的 TRL/RLP—— 介导动脉粥样硬化进展。我们建议通过以下方式检验这一假设并阐明 APOC3 的作用： 将 T1DM 和 MetS/T2DM 小鼠模型中的血浆 APOC3 和/或 TRL/RLP 水平正常化 3 倍 不同的方法；使用 Apoc3 反义寡核苷酸 (ASO)，即 Angptl3 ASO，可减少 TRL 和其他脂蛋白独立于肝脏 Apoc3 表达和 CREB-H 的肝脏表达， 它可以降低 TRL，而不影响 APOC3 的总血浆水平。对比这些治疗的效果 将为 APOC3 与 TRL/RLP 降低的作用提供新的见解。第二个具体目标是 确定富含 APOC3 的 TRL/RLP 介导的焦亡是否有助于病变巨噬细胞 糖尿病死亡和晚期病变。我们建议通过以下方式机械地测试该途径的重要性 使用骨髓细胞中缺乏 caspase 11 及其下游效应子 Gasdermin D 的小鼠。我们也期待 降低糖尿病小鼠的TRL可以预防细胞焦亡。体内研究将得到补充 巨噬细胞机制研究，以阐明糖尿病诱导巨噬细胞的作用途径 死亡，并通过研究解决胰岛素受体信号传导减少导致死亡增加的机制 T1DM 和 MetS/T2DM 模型中 APOC3 的水平。