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

• 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
• 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

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）：人类载脂蛋白（Apo） E包括三种常见的亚型，称为ApoE2， ApoE3和ApoE4。ApoE3被认为是正常的同工异构体，而ApoE2和ApoE4是功能失调的。携带有缺陷的ApoE亚型的个体会出现高胆固醇血症和动脉粥样硬化。同样，ApoE空敲除（ApoE-/-）小鼠患有类似人类疾病的高胆固醇血症和动脉粥样硬化。apoe缺陷患者和小鼠模型的高胆固醇血症主要是由于含有ApoB48的残余脂蛋白血浆水平升高。我们实验室之前的研究表明，从ApoE-/-小鼠中获得的残余脂蛋白能够将巨噬细胞转化为泡沫细胞，并且无ApoE的残余脂蛋白诱导的泡沫细胞形成与真核翻译起始因子21 （eIF-21）的磷酸化增强相吻合，这是与内质网（ER）应激相关的细胞事件。我们还观察到，抑制eIF-21磷酸化可减弱无apoe残余脂蛋白诱导的泡沫细胞形成。此外，我们观察到富含人类ApoE缺陷异构体的小鼠残余脂蛋白，特别是富含ApoE4的小鼠残余脂蛋白，在巨噬细胞中诱导胆固醇积累和eIF-21磷酸化。极有可能的是，在ApoE缺失或缺乏的情况下，残余脂蛋白与巨噬细胞的相互作用激活内质网应激相关的信号通路，进而调节其编码产物有助于泡沫细胞形成的基因的表达。在这个项目中，我们将验证一个假设，即含有人类ApoE缺陷亚型的残余脂蛋白通过诱导内质网应激的机制诱导泡沫细胞形成。我们将用三个具体目标来检验这一假设。特异性目的1将确定携带人类ApoE缺陷同工型的残余脂蛋白是否调节泡沫细胞形成相关基因的表达。特异性目的2将确定携带人类ApoE缺陷亚型的残余脂蛋白是否通过激活内质网应激相关信号通路来调节基因表达。特异性目的3将确定携带人类ApoE缺陷同工型的残余脂蛋白是否通过激活内质网应激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，抑制内质网应激相关信号通路将减弱apoe缺陷残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，并抑制泡沫细胞形成。