Endoplasmic reticulum stress and foam cell formation

内质网应激和泡沫细胞形成

• 批准号: 7878595
• 负责人: ZHONGMAO GUO
• 金额: $ 43.68万
• 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: 2009-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878595
• 关键词: Apolipoprotein E; Apolipoproteins; Arterial Intimas; Atherosclerosis; Attenuated; Binding; Cause of Death; Cells; Cholesterol; Cholesterol Homeostasis; Deposition; Development; Eukaryotic Initiation Factors; Event; Foam Cells; Gene Expression; Genes; Genetic Transcription; Goals; Hydrolase; Individual; Inflammation Mediators; Laboratories; Link; Lipids; Lipoproteins; Molecular; Molecular Chaperones; Mus; Myocardial Infarction; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Plasma; Prevention; Protein Biosynthesis; Proteins; Recruitment Activity; Signal Pathway; Staging; Stroke; Testing; Time; Translations; Work; apolipoprotein B-48; apolipoprotein E-3; design; endoplasmic reticulum stress; human disease; hypercholesterolemia; inhibitor/antagonist; macrophage; monocyte; mouse model; novel; public health relevance; research study; response; treatment strategy; uptake

DESCRIPTION (provided by applicant): Individuals with apolipoprotein (Apo) E deficiency develop hypercholesterolemia and atherosclerosis. Similarly, ApoE-deficient (ApoE-/-) mice elevate plasma ApoB48-carrying lipoproteins and develop atherosclerosis in a manner that resembles the human disease. The primary cause of atherosclerosis in ApoE-deficient patients and mouse models is the deposition of ApoE-deficient, ApoB48-carrying (E-/B48) lipoproteins in the arterial wall. The deposited lipoproteins recruit monocytes into the arterial intima and transform them into macrophages, which participate in the pathogenesis of atherosclerosis mainly through two mechanisms: 1) releasing inflammatory mediators, and 2) forming foam cells. An uncontrolled macrophage uptake of E-/B48 lipoproteins could be a mechanism underlying foam cell formation in ApoE-/- mice. Our laboratory recently demonstrated that E-/B48 lipoproteins reduce cellular cholesterol efflux from macrophages and down-regulates lysosomal hydrolase expression. In addition, the degradation of E-/B48 lipoproteins by macrophages declined over time. These novel findings indicate that both reduced cholesterol efflux and decreased degradation of E-/B48 lipoproteins could contribute to foam cell formation. Our preliminary studies also revealed that incubation of macrophages with E-/B48 lipoproteins enhanced eukaryotic translation initiationfactor 21 (eIF-2a) phosphorylation, which is linked to one of the unfolded protein response (UPR) signaling pathways. Thus, interaction of E-/B48 lipoproteins with macrophages may activate UPR signaling pathways, which in turn regulate gene expression and induce atherogenic events, such as triggering foam cell formation. In the proposed studies, we will test the hypothesis that activation of UPR signaling pathways is a mechanism by which E-/B48 lipoproteins regulate gene expression, induce foam cell formation and promote atherosclerosis. This project includes four specific aims: 1) to determine whether E-/B48 lipoprotein-induced changes in gene expression result from altered transcription or translation or both in mouse macrophages; 2) to determine whether activation of UPR signaling pathways is a mechanism underlying E-/B48 lipoprotein-induced gene expression changes; 3) to determine whether activation of UPR pathways is a mechanism underlying E-/B48 lipoprotein-induced foam cell formation; and 4) to determine the effect of inhibiting eIF-2a phosphorylation on atherosclerosis in ApoE-/- mice. If our hypothesis is correct, inactivation of UPR signaling pathways will attenuate E-/B48 lipoprotein-induced gene expression, and suppress foam cell formation and atherosclerosis development. PUBLIC HEALTH RELEVANCE: Myocardial infarction and stroke are the leading caused of death in the United Sates. Atherosclerosis is the primary cause of myocardial infarction and stroke. Formation of lipid-laden foam cells in the vessel wall is the early stage of atherosclerosis. The goal of this proposal is to determine the involvement of endoplasmic reticulum stress in foam cell formation. Endoplasmic reticulum stress is a cellular event that reduces the level of some proteins but increases the level of other proteins in cells. Our preliminary studies indicate that lipoproteins obtained from mice deficient in apolipoprotein E can cause endoplasmic reticulum stress and induce foam cell formation. The experiments designed in this proposal will study whether endoplasmic reticulum stress is the cause of foam cell formation. Finding from this work should contribute to understanding of the molecular mechanism of foam cell formation, and provide strategies for treatment or prevention of atherosclerosis by inhibition of endoplasmic reticulum stress.

描述（由申请人提供）：载脂蛋白 (Apo) E 缺乏的个体会出现高胆固醇血症和动脉粥样硬化。同样，ApoE 缺陷 (ApoE-/-) 小鼠血浆中携带 ApoB48 的脂蛋白升高，并以类似于人类疾病的方式发展动脉粥样硬化。 ApoE 缺陷患者和小鼠模型中动脉粥样硬化的主要原因是 ApoE 缺陷、携带 ApoB48 (E-/B48) 脂蛋白在动脉壁中沉积。沉积的脂蛋白将单核细胞募集到动脉内膜并将其转化为巨噬细胞，巨噬细胞主要通过两种机制参与动脉粥样硬化的发病机制：1）释放炎症介质，2）形成泡沫细胞。巨噬细胞对 E-/B48 脂蛋白不受控制的摄取可能是 ApoE-/- 小鼠泡沫细胞形成的潜在机制。我们的实验室最近证明，E-/B48 脂蛋白可减少巨噬细胞的细胞胆固醇流出并下调溶酶体水解酶的表达。此外，巨噬细胞对E-/B48脂蛋白的降解随着时间的推移而下降。这些新发现表明，胆固醇流出的减少和 E-/B48 脂蛋白降解的减少可能有助于泡沫细胞的形成。我们的初步研究还表明，巨噬细胞与 E-/B48 脂蛋白的孵育增强了真核翻译起始因子 21 (eIF-2a) 磷酸化，这与未折叠蛋白反应 (UPR) 信号通路之一有关。因此，E-/B48脂蛋白与巨噬细胞的相互作用可能激活UPR信号通路，进而调节基因表达并诱导动脉粥样硬化事件，例如触发泡沫细胞形成。在拟议的研究中，我们将检验以下假设：UPR 信号通路的激活是 E-/B48 脂蛋白调节基因表达、诱导泡沫细胞形成和促进动脉粥样硬化的机制。该项目包括四个具体目标：1) 确定 E-/B48 脂蛋白诱导的基因表达变化是否是由小鼠巨噬细胞中转录或翻译或两者的改变引起的； 2) 确定UPR信号通路的激活是否是E-/B48脂蛋白诱导基因表达变化的潜在机制； 3) 确定UPR途径的激活是否是E-/B48脂蛋白诱导泡沫细胞形成的潜在机制； 4)确定抑制eIF-2a磷酸化对ApoE-/-小鼠动脉粥样硬化的影响。如果我们的假设正确，UPR信号通路的失活将减弱E-/B48脂蛋白诱导的基因表达，并抑制泡沫细胞的形成和动脉粥样硬化的发展。公共卫生相关性：心肌梗塞和中风是美国的主要原因。动脉粥样硬化是心肌梗塞和中风的主要原因。血管壁中富含脂质的泡沫细胞的形成是动脉粥样硬化的早期阶段。该提案的目标是确定内质网应激在泡沫细胞形成中的参与。内质网应激是一种细胞事件，它会降低细胞中某些蛋白质的水平，但会增加其他蛋白质的水平。我们的初步研究表明，从缺乏载脂蛋白E的小鼠中获得的脂蛋白可以引起内质网应激并诱导泡沫细胞形成。本提案设计的实验将研究内质网应激是否是泡沫细胞形成的原因。这项工作的发现应有助于理解泡沫细胞形成的分子机制，并为通过抑制内质网应激来治疗或预防动脉粥样硬化提供策略。

项目成果

Up-regulation of cholesterol absorption is a mechanism for cholecystokinin-induced hypercholesterolemia.

胆固醇吸收的上调是缩胆囊素诱导的高胆固醇血症的机制。

• DOI: 10.1074/jbc.m113.534388
• 发表时间: 2014
• 期刊: The Journal of biological chemistry
• 作者: Zhou,LiChun;Yang,Hong;Okoro,EmmanuelU;Guo,Zhongmao
• 通讯作者: Guo,Zhongmao

Inhibition of endoplasmic reticulum stress and atherosclerosis by 2-aminopurine in apolipoprotein e-deficient mice.

• DOI: 10.1155/2013/847310
• 发表时间: 2013
• 期刊: ISRN pharmacology
• 作者: Zhou L;Yang D;Wu DF;Guo ZM;Okoro E;Yang H
• 通讯作者: Yang H

Apolipoprotein E-Deficient Lipoproteins Induce Foam Cell Formation by Activation of PERK-EIF-2α Signaling Cascade.

载脂蛋白 E 缺陷脂蛋白通过激活 PERK-EIF-2α 信号级联诱导泡沫细胞形成。

• DOI: 10.4172/1948-593x.1000033
• 发表时间: 2010
• 期刊: Journal of bioanalysis & biomedicine
• 作者: Zhao,Yanfeng;Guo,Zhongmao;Lin,Xinghua;Zhou,Lichun;Okoro,EmmanuelU;Fan,Guohuang;Ramaswamy,Raju;Yang,Hong
• 通讯作者: Yang,Hong

A novel function of apolipoprotein E: upregulation of ATP-binding cassette transporter A1 expression.

• DOI: 10.1371/journal.pone.0021453
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhao Y;Chen X;Yang H;Zhou L;Okoro EU;Guo Z
• 通讯作者: Guo Z

Hepatic Endosome Protein Profiling in Apolipoprotein E Deficient Mice Expressing Apolipoprotein B48 but not B100.

表达载脂蛋白 B48 但不表达 B100 的载脂蛋白 E 缺陷小鼠的肝内体蛋白分析。

• DOI: 10.4172/1948-593x.1000031
• 发表时间: 2010
• 期刊: Journal of bioanalysis & biomedicine
• 作者: Chen,Anshu;Guo,Zhongmao;Zhou,Lichun;Yang,Hong
• 通讯作者: Yang,Hong