Anti-inflammatory, cholesterol export, and cardioprotective functions of ABCA1

ABCA1 的抗炎、胆固醇输出和心脏保护功能

基本信息

批准号：
8415968
负责人：
RENEE C LEBOEUF
金额：
$ 39.11万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8415968
关键词：
ATP-Binding Cassette Transporters Amino Acid Motifs Animals Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Apolipoproteins Arteries Atherosclerosis Biochemical Cardiovascular Diseases Cell Culture Techniques Cell Membrane Proteins Cell physiology Cells Cholesterol Development Excision Genetic Engineering Goals Heart Heart Diseases High Density Lipoproteins Hormonal Impairment In Vitro Inflammation Inflammatory Inflammatory Response Janus kinase 2 Link Lipids Mass Spectrum Analysis Metabolism Molecular Morbidity - disease rate Mus Mutagenesis Pathway interactions Peptides Phospholipids Plasma Process Production Property Protein Export Pathway Protein Tyrosine Kinase Proteins Receptor Signaling Research Role STAT3 gene Signal Pathway Site Techniques Testing Therapeutic Therapeutic Effect Therapeutic Intervention Transplantation Western World Wild Type Mouse atherogenesis cardiovascular risk factor clinically relevant cytokine density in vivo insight macrophage mimetics mortality mouse model novel strategies prevent receptor reverse cholesterol transport therapeutic target transcription factor

项目摘要

Atherosclerotic cardiovascular disease (CVD) is the most common cause of mortality and morbidity in the Western world. Cholesterol accumulation in arterial macrophages and inflammation of the artery wall both contribute to development of CVD. There is an inverse relationship between plasma high-density (HDL) levels and cardiovascular risk, implying that factors associated with HDL metabolism are cardioprotective. HDL protects against CVD by several mechanisms that remove cholesterol from arterial cells and suppress inflammation. A major cardioprotective factor associated with HDL metabolism is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that exports cholesterol and phospholipids from cells to lipid-depleted HDL apolipoproteins, such as apoA-I. We found that ABCA1 also functions as an anti-inflammatory signaling receptor through activation of a JAK2/STAT3 pathway, which is independent of cholesterol export activity. Thus, macrophage ABCA1 provides a direct biochemical link between the cardioprotective effects of reverse cholesterol transport and suppressed inflammation. These observations indicate that ABCA1 is an attractive therapeutic target for treating the two major underlying mechanisms that cause CVD. The goal of this project is to determine the cellular processes involved in the cholesterol export and anti-inflammatory activities of ABCA1 and to assess their cardioprotective roles in vivo. We propose to use mutagenesis, biochemical, and mass spectrometric techniques to evaluate the effects of apolipoprotein-ABCA1 interactions on cholesterol export and inflammatory cytokine production and to characterize cellular mechanisms involved. We also propose to use atherosclerosis-susceptible mouse models to determine how these anti-inflammatory and cholesterol export functions of ABCA1 contribute to atherosclerosis in whole animals. This information will define possible sites of impairment of these pathways that may be clinically relevant and uncover potential targets for therapeutic interventions for preventing CVD.

动脉粥样硬化心血管疾病（CVD）是西方死亡率和发病率的最常见原因世界。胆固醇在动脉巨噬细胞中的积累和动脉壁的炎症都有助于 CVD的开发。血浆高密度（HDL）水平与心血管风险，这意味着与HDL代谢相关的因素是心脏保护性的。 HDL保护通过几种从动脉细胞中去除胆固醇并抑制炎症的机制来反对CVD。一个与HDL代谢相关的主要心脏保护因子是ATP结合盒转运蛋白A1（ABCA1），A 细胞膜蛋白将胆固醇和磷脂从细胞中导出到脂质缺失的HDL载脂蛋白，例如apoa-i。我们发现ABCA1还通过激活起作用作为抗炎信号受体 JAK2/STAT3途径，该途径独立于胆固醇出口活动。因此，巨噬细胞ABCA1 在反向胆固醇传输的心脏保护作用和抑制炎症。这些观察结果表明，ABCA1是治疗的有吸引力的治疗靶点引起CVD的两个主要基础机制。该项目的目的是确定细胞 ABCA1的胆固醇出口和抗炎活动涉及的过程并评估其体内心脏保护作用。我们建议使用诱变，生化和质谱技术评估载脂蛋白-ABCA1相互作用对胆固醇导出和炎症细胞因子的影响生产并表征涉及的细胞机制。我们还建议使用动脉粥样硬化易感的小鼠模型确定ABCA1的这些抗炎和胆固醇输出功能如何促进整个动物的动脉粥样硬化。这些信息将定义可能损害这些途径的可能地点可以在临床上相关且发现预防CVD的治疗干预措施的潜在靶标。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Copper chelation by tetrathiomolybdate inhibits vascular inflammation and atherosclerotic lesion development in apolipoprotein E-deficient mice.

DOI：
10.1016/j.atherosclerosis.2012.06.013
发表时间：
2012-08
期刊：
ATHEROSCLEROSIS
影响因子：
5.3
作者：
Wei, Hao;Zhang, Wei-Jian;McMillen, Timothy S.;LeBoeuf, Renee C.;Frei, Balz
通讯作者：
Frei, Balz

The effect of oral l-carnitine on lipoprotein composition in the Watanabe Heritable Hyperlipidemic Rabbit (Oryctolagus cuniculus).

DOI：
10.1016/0300-9629(87)90071-5
发表时间：
1987
期刊：
Comparative biochemistry and physiology. A, Comparative physiology
影响因子：
0
作者：
T. L. Raymond;S. A. Reynolds;J. A. Swanson;C. Patnode;F. Bell
通讯作者：
T. L. Raymond;S. A. Reynolds;J. A. Swanson;C. Patnode;F. Bell

Effects of acceptor composition and mechanism of ABCG1-mediated cellular free cholesterol efflux.

DOI：
10.1194/jlr.m800362-jlr200
发表时间：
2009-02
期刊：
JOURNAL OF LIPID RESEARCH
影响因子：
6.5
作者：
Sankaranarayanan, Sandhya;Oram, John F.;Asztalos, Bela F.;Vaughan, Ashley M.;Lund-Katz, Sissel;Adorni, Maria Pia;Phillips, Michael C.;Rothblat, George H.
通讯作者：
Rothblat, George H.