Regulated Expression of Myeloperoxidase in Atherosclerosis

动脉粥样硬化中髓过氧化物酶的表达调节

基本信息

批准号：
7616208
负责人：
WANDA F REYNOLDS
金额：
$ 7.76万
依托单位：
SIDNEY KIMMEL CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-20 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7616208
关键词：
Agonist Alleles Alu Elements Arterial Fatty Streak Atherosclerosis Binding Binding Sites Bioavailable Biological Availability Blood Pressure Bone Marrow Cardiovascular Diseases Chloride Ion Chlorides Cholesterol Chronic Complex Deposition Development Diet Disease Drug Delivery Systems Dyslipidemias Endothelium Enzymes Estrogen Receptor 1 Estrogen Receptors Estrogens Fatty acid glycerol esters Female Foam Cells Gene Expression Genes Genetic Genetic Polymorphism Glucose High Density Lipoproteins Homeostasis Human Human Genetics Hydrogen Peroxide Hyperlipidemia Hyperphagia Hypochlorous Acid Impairment Implant Inflammatory Inflammatory Response Insulin Resistance Investigation Laboratories Lesion Leukocytes Life Style Ligands Lipids Lipoproteins Low Density Lipoprotein Receptor Low Density Lipoprotein oxidation Mass Spectrum Analysis Metabolic Modeling Molecular Monitor Mus Myeloid Cells Nuclear Receptors Obesity Oxidants Peroxidases Peroxisome Proliferator-Activated Receptors Play Primates RXR Reaction Regulation Regulator Genes Risk Factors Role Serum Site Tablets Testing Transgenes Transgenic Mice Transgenic Organisms Transplantation Triglycerides Vasodilation Weight Gain atheroprotective cell type feeding in vivo lipid metabolism mRNA Expression macrophage male mouse model novel novel therapeutics oxidation prevent promoter receptor receptor binding reverse cholesterol transport rosiglitazone tool uptake

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease in which macrophages infiltrate the arterial wall, releasing myeloperoxidase (MPO), an oxidant-generating enzyme. Oxidation of LDL increases its uptake by macrophages to create lipid laden foam cells. The efflux of cholesterol from foam cells is impaired by MPO oxidation of apoA1, resulting in dysfunctional HDL. MPO expression is governed in part by a functional promoter polymorphism, -463G/A, which alters expression levels, and is associated with increased atherosclerosis, serum cholesterol, triglycerides and weight gain/obesity, both in human studies and in mouse models of atherosclerosis. The -463G/A polymorphism is situated in an Alu, within a cluster of nuclear receptor binding sites, including sites for PPAR?, estrogen receptor, and LXR. PPAR? strongly induces human MPO expression in macrophages, while estrogen receptor binds an overlapping site, blocking PPAR? binding and activity. LXR binds the middle site and downregulates human MPO gene expression in cultured macrophages. Mouse models are an important tool by which to investigate the regulation of MPO in vivo, and its effects on atherosclerosis. However, the mouse MPO gene is not expressed in lesions, therefore existing models cannot be used to study the role of MPO. To circumvent this problem, we generated transgenic mice expressing the human MPO gene, and crossed these to the LDLR-/- model for atherosclerosis. On a high fat Western diet, these transgenics developed larger lesions, increased serum cholesterol, triglycerides, and glucose, correlating with excessive weight gain/obesity. Here we propose to use these human MPO transgenics to determine if PPAR?, estrogen receptor, or LXR regulate human MPO gene expression in vivo in atherosclerosis lesions, and determine if such regulation impacts the development of atherosclerosis or hyperlipidemia. Aim 1 is an investigation of the effects of PPAR? and estrogen receptor on MPO expression and its effects. Aim 2 examines the effects of LXR, a key modulator of lipid metabolism, on MPO expression and its effects. A subaim will investigate the effects of statins, atheroprotective agents which downregulate MPO expression in macrophages.

描述（由申请人提供）：动脉粥样硬化是一种慢性炎症性疾病，其中巨噬细胞渗入动脉壁，释放出骨过氧化物酶（MPO），一种氧化剂生成酶。 LDL的氧化增加了巨噬细胞的吸收，从而产生了脂质的脂肪泡沫细胞。 APOA1的MPO氧化会损害泡沫细胞中胆固醇的外流，导致功能障碍HDL。 MPO表达部分由功能启动子多态性-463G/A（改变表达水平），与动脉粥样硬化，血清胆固醇，甘油三酸酯和体重增加/肥胖有关，在人类研究和动脉粥样硬化小鼠模型中都与动脉粥样硬化，血清胆固醇，甘油三酸酯和体重增加/肥胖有关。 -463G/A多态性位于ALU中，在一个核受体结合位点，包括PPAR？，雌激素受体和LXR的位点。 ppar？强烈诱导人类MPO在巨噬细胞中的表达，而雌激素受体结合重叠位点，阻止PPAR？结合和活性。 LXR结合中间位点并下调培养的巨噬细胞中人类MPO基因的表达。小鼠模型是研究MPO在体内调节及其对动脉粥样硬化的影响的重要工具。但是，小鼠MPO基因在病变中未表达，因此现有模型不能用于研究MPO的作用。为了解决这个问题，我们产生了表达人MPO基因的转基因小鼠，并将其跨越了动脉粥样硬化的LDLR - / - 模型。在高脂肪的西方饮食中，这些转基因会出现更大的病变，血清胆固醇，甘油三酸酯和葡萄糖的增加，与体重增加/肥胖过度相关。在这里，我们建议使用这些人类MPO转基因学来确定PPAR？，雌激素受体或LXR是否调节动脉粥样硬化病变中体内的人类MPO基因表达，并确定这种调节是否影响动脉粥样硬化或高脂血症的发展。目标1是对PPAR的影响的研究吗？和雌激素受体对MPO表达及其作用。 AIM 2检查了LXR（脂质代谢的关键调节剂）对MPO表达及其效果的影响。 Subaim将研究他汀类药物的作用，汀类药物的影响，该毒剂在巨噬细胞中下调MPO的表达。