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Mechanisms for Dysfunctional HDL Formation in Familial Hypercholesterolemia

家族性高胆固醇血症 HDL 形成功能障碍的机制

基本信息

批准号：
8396789
负责人：
MACRAE F LINTON
金额：
$ 47.12万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-23 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8396789
关键词：
Affect Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Arachidonic Acids Arterial Fatty Streak Atherosclerosis Attention Binding Blood Component Removal Cardiovascular system Carotid Atherosclerotic Disease Cell membrane Cholesterol Cholesterol Homeostasis Complex Coronary Arteriosclerosis Coronary artery Development Diabetes Mellitus Dinoprostone Disease Eicosanoid Receptor Employee Strikes Enzymes Epidemiology Event F2-Isoprostanes Familial Hypercholesterolemia Functional disorder Goals High Density Lipoprotein Cholesterol High Density Lipoproteins Human Inflammation Inflammatory Inflammatory Response Isoprostanes LDL Cholesterol Lipoproteins LDLR gene Lead Lipid Peroxidation Lipids Lipoproteins Low-Density Lipoproteins Lysine Measures Mediating Mediation Mediator of activation protein Metabolic syndrome Modification Mutation Oxidants Pathogenesis Patients Phospholipids Plasma Play Property Proteins Reactive Oxygen Species Reporting Rheumatoid Arthritis Risk Role Systemic Lupus Erythematosus Testing Thromboxane Receptor Very low density lipoprotein adduct amino group atherogenesis atheroprotective atherothrombosis cardiovascular risk factor crosslink disorder risk improved in vivo ketoaldehyde macrophage novel marker oxidant stress oxidation oxidative damage oxidized low density lipoprotein premature prostaglandin EP2 receptor protein crosslink reverse cholesterol transport

项目摘要

DESCRIPTION (provided by applicant): Anti-atherogenic functions of HDL include mediation of reverse cholesterol transport, and anti-oxidative and anti- inflammatory effects. Mounting evidence supports the concept that HDL function can be impaired or lost, and that dysfunctional HDL contributes to the development of atherosclerosis. Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with severely elevated LDL levels and increased risk of premature coronary artery disease (CAD). Both heterozygous and homozygous FH have low HDL, but this finding has not received much attention, and the increased CAD risk is attributed to the elevated LDL levels. We have recently discovered that the HDL from patients with FH is dramatically pro-inflammatory. A goal of this proposal (Specific Aim 1) is to examine the hypothesis that HDL of FH patients is dysfunctional (pro-inflammatory, pro- oxidant, and/or associated with reduced efflux capacity). Isoprostanes are formed from the non-enzymatic oxidation of arachidonic acid in phospholipids of lipoproteins and cell membranes. Plasma levels of F2- isoprostanes are established in vivo markers of lipid peroxidation and oxidant stress. Interestingly, the esterified isosprostanes, (EIs) in human plasma are mainly localized to HDL, with lesser amounts associated with LDL and VLDL. Several lines of evidence support a direct role for lipid peroxidation and/or F2-isoprostanes in atherosclerotic lesion development. At present it is unknown whether the accumulation of EIs in HDL affects its atheroprotective functions. Interestingly, we have found that plasma from subjects with FH undergoing LDL apheresis has twice the amount of EIs compared to normal plasma, and that after LDL apheresis EI levels decrease by 45%. Isolevuglandins (isoLGs) are a group of g-ketoaldehydes (isoketals) that are highly reactive mediators of oxidative damage formed in parallel with isoprostanes. We will investigate whether these bioactive lipids play direct mechanistic roles in the pro-inflammatory properties of HDL in FH patients. In Specific Aim 2, we will examine the hypothesis that accumulation of bioactive lipids (F2-isoprostanes and Isolevuglandins) in HDL results in loss of anti-inflammatory function. Isoprostanes have been shown to bind to eicosanoid receptors implicated in atherogenesis, including receptors for thromboxane (TP) and prostaglandin (PG)E2 (EP2). Therefore, we will examine the hypothesis that the TP and EP2 receptors contribute to the inflammatory effects of F2-isoprostane enriched HDL. Isoketals rapidly adduct to the e-amino groups of lysines on proteins, promoting protein cross-linking and dysfunction. Therefore, we will examine the hypothesis that isolevuglandins mediate oxidative damage of HDL associated proteins resulting in impaired function of HDL cholesterol. Our results may lead to the development of new markers of HDL function, provide new pharmacologic targets for improving HDL function, and identify HDL as a target of therapy in FH patients. PUBLIC HEALTH RELEVANCE: We have recently discovered that HDL from patients with Familial Hypercholesterolemia is strikingly pro- inflammatory. The goal of Specific Aim 1 of this proposal is to examine the hypothesis that HDL is dysfunctional (pro-inflammatory, pro-oxidant, and/or associated with reduced efflux capacity) in FH. In Specific Aim 2, we will examine the hypothesis that accumulation of bioactive lipids (F2-isoprostanes and Isolevuglandins) in HDL results in loss of anti-inflammatory function.