Cardioprotective Mechanisms of HDL

HDL 的心脏保护机制

• 批准号: 8323850
• 负责人: JAY W HEINECKE
• 金额: $ 43.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-16 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323850
• 关键词: Acute-Phase Reaction; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein A-I; Arteries; Atherosclerosis; CETP gene; Cardiovascular Diseases; Cause of Death; Cells; Cholesterol; Clinical Research; Complex; Coronary Arteriosclerosis; Development; Dietary Intervention; Employee Strikes; Engineering; Event; Gene Expression; Genes; Genetic Variation; Genetically Engineered Mouse; Goals; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Inflammation; Inflammatory; Interferon Type I; Interferons; Lead; Link; Macrophage Activation; Mediator of activation protein; Metabolism; Metric; Molecular; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Phenotype; Plasma; Play; Population; Property; Proteins; Proteome; Proteomics; Role; Serum; Signal Transduction; Sterols; TLR4 gene; Testing; Therapeutic; Therapeutic Intervention; Vascular Diseases; Wild Type Mouse; atheroprotective; cardiovascular disorder risk; diabetic cardiomyopathy; disorder risk; human disease; in vivo; inhibitor/antagonist; interest; macrophage; mouse model; novel therapeutic intervention; prevent; response; septic; therapy design; translational study

DESCRIPTION (provided by applicant): In mouse models of atherosclerosis, HDL is thought to be atheroprotective because it removes excess cholesterol from macrophages of the artery wall and inhibits inflammation. We have shown that HDL inhibits a specific inflammatory pathway in macrophages - the type I interferon response pathway - that is regulated by TLR4-TRAM signaling. We also have demonstrated that elevated levels of the acute-phase response proteins SAA1 and SAA2 (SAA1/2) in human HDL associate with impaired sterol efflux from macrophages. Recent studies demonstrate that the sterol efflux capacity of human serum HDL strongly associates with CAD status but is independent of HDL-cholesterol and protein (apoA-I) levels. Thus, the cholesterol efflux capacity of serum HDL might be a marker-and perhaps mediator-of atherosclerotic burden that is independent of HDL- C and apoA-I. Changes in the HDL proteome could alter its ability to remove cellular cholesterol or inhibit macrophage inflammation. We therefore will test the hypotheses that (a) HDL prevents macrophage activation by inhibiting the TLR4-TRAM pathway and (b) altered levels of pro- and anti-inflammatory proteins render HDL dysfunctional in mice and humans. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CAD) is the leading cause of death in industrialized Western populations. Moreover, inflammation-a central theme of this proposal-is implicated in the pathogenesis of many other human diseases. The population at large might benefit from the proposed studies because we may identify ways to identify subjects at risk for CAD, which might lead to preventative treatment. In the long-term, it is possible that the studies outlined in this proposal might lead to the development of new therapeutic interventions designed to prevent or treat CAD.

描述（由申请人提供）：在动脉粥样硬化小鼠模型中，HDL被认为具有动脉粥样硬化保护作用，因为它可以从动脉壁的巨噬细胞中清除过量的胆固醇并抑制炎症。我们已经表明，HDL抑制巨噬细胞中的特定炎症途径-I型干扰素反应途径-这是由TLR 4-TRAM信号调节。我们还证明了人HDL中急性期反应蛋白SAA 1和SAA 2（SAA 1/2）水平升高与巨噬细胞的甾醇流出受损相关。最近的研究表明，人血清HDL的固醇流出能力与CAD状态密切相关，但与HDL-胆固醇和蛋白质（apoA-I）水平无关。因此，血清HDL的胆固醇外排能力可能是一个标记物，也可能是动脉粥样硬化负荷的介导物，它不依赖于HDL-C和apoA-I。HDL蛋白质组的变化可以改变其清除细胞胆固醇或抑制巨噬细胞炎症的能力。因此，我们将测试以下假设：（a）HDL通过抑制TLR 4-TRAM通路来防止巨噬细胞活化和（B）促炎蛋白和抗炎蛋白水平的改变使小鼠和人类中HDL功能障碍。 公共卫生相关性：心血管疾病（CAD）是西方工业化人群的主要死亡原因。此外，炎症-这一提议的中心主题-与许多其他人类疾病的发病机制有关。大部分人群可能会从拟议的研究中受益，因为我们可以确定识别CAD风险受试者的方法，这可能会导致预防性治疗。从长远来看，本提案中概述的研究可能会导致旨在预防或治疗CAD的新治疗干预措施的开发。