Defective isoforms of ApoE induce atherogenesis via unfolded protein responses

ApoE 的缺陷异构体通过未折叠的蛋白质反应诱导动脉粥样硬化形成

基本信息

批准号：
7692453
负责人：
HONG YANG
金额：
$ 32.96万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7692453
关键词：
African American Animal Model ApoE knockout mouse Apolipoprotein E Apolipoproteins Applications Grants Area Atherosclerosis Attenuated Award Binding Cardiovascular Diseases Cardiovascular system Catabolism Cholesterol Coronary heart disease Credentialing Data Development Endoplasmic Reticulum Eukaryotic Initiation Factors Event Foam Cells Funding Gene Expression Genes Goals Grant Human Individual Knock-out Knowledge Laboratories Lipids Lipoproteins Mainstreaming Manuscripts Minority Mission Molecular Mus Myocardial Infarction Patients Phosphorylation Plasma Protein Isoforms Proteins Publications Publishing Research Resources Signal Pathway Staging Stroke Students Testing Therapeutic United States National Institutes of Health Yang apolipoprotein B-48 apolipoprotein E-3 apolipoprotein E-4 atherogenesis career endoplasmic reticulum stress human disease hypercholesterolemia macrophage medical schools mouse model public health relevance response skills uptake

项目摘要

DESCRIPTION (provided by applicant): Human apolipoprotein (Apo) E includes three common isoforms known as ApoE2, ApoE3 and ApoE4. ApoE3 is considered to be the normal isoform, while ApoE2 and ApoE4 are dysfunctional. Individuals carrying defective isoforms of ApoE develop hypercholesterolemia and atherosclerosis. Similarly, ApoE null knockout (ApoE-/-) mice suffer from hypercholesterolemia and atherosclerosis resembling the human disease. The hypercholesterolemia in ApoE-deficient patients and mouse models results mainly from an increased plasma level of remnant lipoproteins that contain ApoB48. Previous studies from our laboratory demonstrate that the remnant lipoproteins obtained from ApoE-/- mice is able to transform macrophages into foam cells, and that foam cell formation induced by ApoE-free remnant lipoproteins coincides with an enhanced phosphorylation of eukaryotic translation initiation factor 21 (eIF-21), which is a cellular event related to endoplasmic reticulum (ER) stress. We also observed that inhibition of eIF-21 phosphorylation attenuated ApoE-free remnant lipoprotein-induced foam cell formation. Moreover, we observed that mouse remnant lipoproteins enriched with defective isofoms of human ApoE, especially those enriched with ApoE4, induced cholesterol accumulation and eIF-21 phosphorylation in macrophages. It is highly likely that in the absence of, or deficiency in, ApoE, interaction of remnant lipoproteins with macrophages activates ER stress-related signaling pathways, which in turn regulate the expression of genes whose encoded products contribute to foam cell formation. In this project, we will test a hypothesis that the remnant lipoproteins that contain defective isoforms of human ApoE induce foam cell formation via a mechanism involving induction of ER stress. We will test this hypothesis with three specific aims. Specific aim 1 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE regulate the expression of genes related to foam cell formation. Specific aim 2 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE regulate gene expression by activation of ER stress-related signaling pathways. Specific aim 3 will determine whether the remnant lipoproteins carrying defective isoforms of human ApoE induce foam cell formation by activation of ER stress-related signaling pathways. If our hypothesis is correct, inhibition of ER stress-related signaling pathways would attenuate ApoE-deficient remnant lipoprotein-induced changes in macrophage lipid catabolism and foam cell formation-related gene expression, and suppress foam cell formation. PUBLIC HEALTH RELEVANCE: This proposal studies the involvement of unfolded protein response in foam cell formation, an early stage of atherosclerosis. Data derived from this project will contribute to understanding of the mechanism of atherosclerosis, and provide therapeutic strategies for myocardial infarction and stroke induced by atherosclerosis.

描述（由申请人提供）：人载脂蛋白（APO）E包括三种称为APOE2，APOE3和APOE4的常见同工型。 APOE3被认为是正常的同工型，而APOE2和APOE4功能障碍。携带APOE的同工型有缺陷的个体会出现高胆固醇血症和动脉粥样硬化。同样，ApoE Null敲除（APOE - / - ）小鼠患有高胆固醇血症和类似于人类疾病的动脉粥样硬化。 APOE缺陷患者和小鼠模型的高胆固醇血症主要来自含有APOB48的残余脂蛋白的血浆水平升高。我们实验室的先前研究表明，从ApoE - / - 小鼠获得的残留脂蛋白能够将巨噬细胞转化为泡沫细胞，并且由无apoe无含量残留的脂蛋白诱导的泡沫细胞形成与爱无核转化因子21（EIF-21）的磷酸化的磷酸化增强，这是一个依赖的事件。我们还观察到，抑制EIF-21磷酸化减弱了无APOE残留脂蛋白诱导的泡沫细胞的形成。此外，我们观察到，富含人APOE的异卵泡的小鼠残留脂蛋白，尤其是那些富含APOE4，诱导的胆固醇积累和巨噬细胞中EIF-21磷酸化的小鼠脂蛋白。在不存在或缺乏APOE的情况下，残留脂蛋白与巨噬细胞的相互作用激活了与ER应力相关的信号通路，这反过来又调节其编码产物有助于泡沫细胞形成的基因的表达。在该项目中，我们将检验一个假设，即含有人ApoE的缺陷同工型的残留脂蛋白通过涉及诱导ER应激的机制诱导泡沫细胞的形成。我们将以三个特定的目标检验这一假设。具体目标1将确定携带人apoE的缺陷同工型的残留脂蛋白是否调节与泡沫细胞形成相关的基因的表达。具体目标2将确定携带人APOE的缺陷同工型的残留脂蛋白是否通过激活与ER应力相关信号通路来调节基因表达。具体目标3将确定携带人APOE的缺陷同工型的残留脂蛋白是否通过激活与ER应力相关信号通路诱导泡沫细胞形成。如果我们的假设是正确的，则抑制与ER应力相关的信号通路的抑制作用将减轻APOE缺陷的残留脂蛋白诱导的巨噬细胞脂质分解代谢和泡沫细胞形成相关基因表达的变化，并抑制泡沫细胞的形成。公共卫生相关性：该提案研究了展开的蛋白质反应参与泡沫细胞形成，这是动脉粥样硬化的早期阶段。从该项目得出的数据将有助于理解动脉粥样硬化的机理，并为动脉粥样硬化引起的心肌梗塞和中风提供治疗策略。