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（T1 DM）、2型糖尿病（T2 DM）和代谢综合征（MetS;也 称为糖尿病前期）增加动脉粥样硬化的风险，这是心血管疾病（CVD）的主要原因 糖尿病患者中的事件和死亡。即使用他汀类药物治疗有效降低LDL胆固醇， 与CVD风险增加有关，与富含甘油三酯的脂蛋白（TRL）代谢异常有关 及其残余脂蛋白颗粒（RLP）。因此，提高TRL清除率的新策略 最近引起了极大的兴趣，特别是在糖尿病的情况下。该应用程序使用三个 增加糖尿病中TRL和RLP清除率的策略; i）抑制载脂蛋白C3（APOC 3），ii） 血管生成素样3（ANGPTL 3）的抑制，和iii）转录的活性形式的肝表达 因子CREB-H（cAMP反应元件结合蛋白H）。拟议的研究建立在强大的初步 数据表明糖尿病加速了晚期病变的进展， TRL水平可预防糖尿病小鼠的动脉粥样硬化。此外，糖尿病导致巨噬细胞增加 死亡与细胞胆固醇积累和caspase 11激活相关，我们假设 导致更晚期的动脉粥样硬化病变表型。总的来说，我们的观察支持 以下假设：糖尿病通过增加APOC 3加速晚期动脉粥样硬化， 相关的TRL和RLP，这反过来又诱导巨噬细胞脂质负荷，并加剧死亡， 巨噬细胞死亡这种机制可以帮助解释心血管疾病风险增加的受试者 糖尿病第一个具体目标将解决糖尿病是否需要富含APOC 3的TRL/RLP- 介导的动脉粥样硬化进展。我们建议验证这一假设，并阐明APOC 3的作用， 在T1 DM和MetS/T2 DM小鼠模型中，通过三种方法使血浆APOC 3和/或TRL/RLP水平标准化 不同的方法;使用Apoc 3反义寡核苷酸（阿索），Angptl 3阿索，其减少了 TRL和其他脂蛋白独立于肝Apoc 3表达，以及CREB-H的肝表达， 其降低TRL而不影响APOC 3的总血浆水平。对比这些治疗的效果 将为APOC 3与TRL/RLP降低的作用提供新的见解。第二个具体目标将 确定由富含APOC 3的TRL/RLP介导的焦亡是否有助于损伤巨噬细胞 死亡和糖尿病的晚期病变。我们建议通过以下方式来机械地测试这一途径的重要性： 使用缺乏胱天蛋白酶11和其下游效应物gasdermin D的小鼠，在骨髓细胞中。我们也期待 在糖尿病小鼠中，通过降低TRL可以预防焦亡。体内研究将通过以下方式进行补充： 巨噬细胞中的机制研究，以阐明糖尿病诱导的巨噬细胞中的通路 死亡，并通过研究解决机制，其中减少胰岛素受体信号传导导致增加 在T1 DM和MetS/T2 DM模型中的APOC 3水平。