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.

动脉粥样硬化性心血管疾病（CVD）是西方国家最常见的死亡和发病原因世界。动脉巨噬细胞中的胆固醇积累和动脉壁的炎症都有助于 CVD的发展。血浆高密度脂蛋白 (HDL) 水平与心血管风险，这意味着与 HDL 代谢相关的因素具有心脏保护作用。 HDL 保护通过清除动脉细胞中的胆固醇并抑制炎症的多种机制来对抗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)，将胆固醇和磷脂从细胞输出到脂质耗尽的 HDL 载脂蛋白的细胞膜蛋白，例如apoA-I。我们发现 ABCA1 还可以通过激活发挥抗炎信号受体的作用 JAK2/STAT3 通路，独立于胆固醇输出活性。因此，巨噬细胞 ABCA1 提供了反向胆固醇转运和心脏保护作用之间的直接生化联系抑制炎症。这些观察结果表明 ABCA1 是一个有吸引力的治疗靶点导致 CVD 的两个主要潜在机制。该项目的目标是确定细胞参与 ABCA1 的胆固醇输出和抗炎活性的过程并评估其体内的心脏保护作用。我们建议使用诱变、生化和质谱技术评估载脂蛋白-ABCA1 相互作用对胆固醇输出和炎症细胞因子的影响生产并表征所涉及的细胞机制。我们还建议使用动脉粥样硬化易感药物小鼠模型以确定 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。该信息将定义这些通路可能受损的位点，可能具有临床相关性，并揭示预防 CVD 治疗干预的潜在目标。

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.