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Oxidant resistant apoA1 in reverse cholesterol transport, inflammation and atherosclerosis

抗氧化剂 apoA1 在逆转胆固醇转运、炎症和动脉粥样硬化中的作用

基本信息

批准号：
9451333
负责人：
Jonathan D Smith
金额：
$ 39.63万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-23 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9451333
关键词：
ATP binding cassette transporter 1 Acute-Phase Reaction Affinity Aftercare Anti-inflammatory Apolipoproteins Area Arterial Fatty Streak Atherosclerosis Bone Marrow Breeding Cell Adhesion Molecules Cell Membrane Proteins Cell Proliferation Cells Cholesterol Collagen Complete Blood Count Coronary Arteriosclerosis Data Development Endothelial Cells Endotoxins Environment Enzymes Epitopes Event Excretory function Gene Chips Gene Expression Profiling Genetic screening method Goals High Density Lipoprotein Cholesterol High Density Lipoproteins Human Human Genetics Impairment Individual Inflammation Inflammatory Knowledge Lead Lesion Lipids Lipoproteins Liver Measures Mediating Modeling Modification Monoclonal Antibodies Monocytosis Mus Myeloid Cells NF-kappa B Names Necrosis Neutrophilia Oxidants Oxides Pathway interactions Peripheral Peroxidases Pharmaceutical Preparations Phenylalanine Phospholipids Plasma Play Protein Isoforms Proteins Randomized Recombinants Reporting Resistance Risk Role Sepsis Series Site-Directed Mutagenesis Smooth Muscle Actin Staining Method Stimulus Testing Therapeutic Tissues Transgenic Mice Triglycerides Tryptophan Variant Zymosan antimicrobial atheroprotective cardiovascular disorder risk comparative efficacy cytokine disorder risk epidemiology study genetic variant histological stains humanized monoclonal antibodies loss of function macrophage monocyte mouse model neutrophil novel overexpression oxidation particle polymicrobial sepsis prevent protective effect reverse cholesterol transport therapeutic target

项目摘要

Abstract High levels of high density lipoprotein-cholesterol (HDL-C) are associated with lowered risk for cardiovascular disease (CVD) in epidemiological studies. Although several mechanisms may play a role in HDL’s protective effect, HDL and its major protein constituent, apolipoprotein-AI (apoA1), are critical components of the reverse cholesterol transport (RCT) pathway, in which cholesterol is removed from peripheral tissues and transferred to the liver for excretion. In the first step of the RCT pathway, lipid-poor apoA1 acts as an acceptor for cell cholesterol and phospholipids via the cell membrane protein ABCA1, generating nascent HDL. However, not all HDL is equivalent, and several studies have reported that individuals with coronary artery disease have HDL that is “dysfunctional” and no longer atheroprotective. The atherosclerotic lesion is a highly oxidative environment, and human lesions contain high levels of the antimicrobial enzyme myeloperoxidase (MPO), which we and others have shown can oxidize apoA1 and impair its function. We determined that the four tryptophan residues in human apoA1 (h-apoA1) are crucial in its MPO mediated loss of cholesterol acceptor function. We created a novel 4WF h-apoA1 variant, in which all four tryptophan residues are replaced by phenylalanine, which is resistant to MPO-mediated loss of function. We created and characterized transgenic mice that express high levels of the 4WF h-apoA1 isoform and found that these mice were resistant to inflammation. We also created human MPO transgenic mice, which over express MPO that can be further induced by zymosan treatment. Here we propose to characterize h-apoA1 modifications in mouse models and if these are modulated by inflammatory stimuli. We will also test whether the oxidant resistant 4WF apoA1 isoform can better protect from inflammation and sepsis, promote reverse cholesterol transport, delay atherosclerosis progression, and promote atherosclerosis regression in mice that over express MPO, creating an oxidative environment similar to that found in human lesions. Mechanistically, we will determine how the 4WF isoform protects mice from an acute phase response, and examine if the 4WF isoform better prevents myeloid cell proliferation and mobilization from the bone marrow leading to monocytosis and neutrophilia that are associated with atherosclerosis progression.

摘要