Impact of Oxidative Modification on HDL Function

氧化修饰对 HDL 功能的影响

• 批准号: 9353659
• 负责人: Rebecca L. Schill
• 金额: $ 2.69万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-03-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353659
• 关键词: 4 hydroxynonenal; Acrolein; Aldehydes; Alpha Particles; Antiatherogenic; Arteries; Atherosclerosis; Biology; Blood Circulation; Cardiovascular Diseases; Cholesterol; Cholesterol Esters; Chronic; Data; Development; Diagnostic; Environmental Risk Factor; Excretory function; Exposure to; Foam Cells; Future; Genes; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Impairment; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Lead; Lesion; Light; Lipid Peroxidation; Lipid Peroxides; Lipids; Lipoproteins; Measures; Mediating; Modeling; Modification; Mus; Mutation; Outcome Study; Oxidative Stress; Oxides; Pathway interactions; Patients; Peritoneal Macrophages; Physiological; Process; Property; Research; Risk; Role; Signal Transduction; Stress; Testing; Therapeutic; Time; atherogenesis; base; cardiovascular disorder prevention; cardiovascular disorder risk; cigarette smoking; clinical development; clinical diagnostics; combat; cytokine; design; experimental study; high density lipoprotein receptor; in vivo; insight; low density lipoprotein inhibitor; macrophage; migration; novel; novel therapeutic intervention; oxidized LDL receptors; oxidized low density lipoprotein; particle; prevent; therapeutic target

PROJECT SUMMARY High circulating levels of high-density lipoprotein (HDL)-cholesterol (HDL-C) have been correlated with a decreased risk in cardiovascular disease (CVD). However, recent studies have demonstrated that HDL function, and not HDL-C levels, may be a more important indicator for CVD risk. During times of chronic inflammation and/or prolonged circulation, HDL is susceptible to oxidative modification. The long-term goal of these studies is to better understand how oxidative modification to HDL compromises its anti-atherogenic functions and generates a pro-atherogenic particle. Our preliminary data indicate that oxidative modification of HDL by either acrolein (acro; major component of cigarette smoke) or 4-hydroxynoneal (HNE; product of lipid peroxidation) results in impaired cholesterol transport functions. Based on these data, we have designed experiments to test the overall hypothesis that oxidized forms of HDL promote pathways that lead to atherogenesis. In Aim 1, we hypothesize that modification of HDL with HNE- and/or acrolein generates a particle that has pro-atherogenic effects on macrophages. We will determine whether acro- and/or HNE- modified HDL can induce the expression of pro-inflammatory cytokines in macrophages, similar to oxidized LDL (oxLDL). Further, we will also determine whether our modified forms of HDL can inhibit macrophage migration. In Aim 2, we will determine if the oxLDL receptor, CD36, can also function as a dysfunctional HDL receptor in macrophages. First, we will test the hypothesis that cholesteryl ester (CE) delivery from oxidized forms of HDL to macrophages is mediated by CD36. Second, we will determine whether acro- and/or HNE- modified HDL can induce CD36-mediated signaling cascades. In Aim 3, we hypothesize that SR-BI deficiency, a model of high HDL-C and impaired clearance of HDL-C due to lack of the HDL receptor, produces dysfunctional HDL particles in vivo. In order to test this novel hypothesis, we will first determine whether HDL isolated from SR-BI-null mice contains oxidative modifications. Next, we will test whether HDL from SR-BI-null mice promotes accumulation of cholesterol in macrophages, and induces pro-inflammatory responses while inhibiting macrophage migration. Together, these studies will shed light on how oxidative modifications to HDL can promote pathways that lead to atherogenesis. We anticipate that the findings from our studies will provide novel insight towards understanding the complexity of HDL function, and may lead to the identification of potential therapeutic targets to combat atherosclerosis.

项目总结