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：
8020964
负责人：
RENEE C LEBOEUF
金额：
$ 41.5万
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 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8020964
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 Engineering Excision 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 public health relevance receptor reverse cholesterol transport therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: HDL protects against heart disease by removing artery-blocking cholesterol from arterial cells and inhibiting inflammation. A cell protein called ABCA1 can perform both of these heart-protecting functions. This research will investigate the cell pathways involved in the cholesterol removal and anti-inflammatory actions of ABCA1 and determine if these pathways protect against heart disease in animals.

描述（由申请人提供）：动脉粥样硬化性心血管疾病（CVD）是西方世界最常见的死亡和发病原因。动脉巨噬细胞中的胆固醇积累和动脉壁的炎症都会导致心血管疾病的发生。血浆高密度脂蛋白 (HDL) 水平与心血管风险之间存在负相关关系，这意味着与 HDL 代谢相关的因素具有心脏保护作用。 HDL 通过多种机制清除动脉细胞中的胆固醇并抑制炎症，从而预防 CVD。与 HDL 代谢相关的一个主要心脏保护因子是 ATP 结合盒转运蛋白 A1 (ABCA1)，它是一种细胞膜蛋白，可将细胞中的胆固醇和磷脂输出至脂质耗尽的 HDL 载脂蛋白，例如 apoA-I。我们发现 ABCA1 还通过激活 JAK2/STAT3 通路发挥抗炎信号受体的作用，该通路与胆固醇输出活性无关。因此，巨噬细胞 ABCA1 在反向胆固醇转运的心脏保护作用和抑制炎症之间提供了直接的生化联系。这些观察结果表明 ABCA1 是治疗引起 CVD 的两种主要潜在机制的有吸引力的治疗靶点。该项目的目标是确定参与 ABCA1 胆固醇输出和抗炎活性的细胞过程，并评估它们在体内的心脏保护作用。我们建议使用诱变、生化和质谱技术来评估载脂蛋白-ABCA1 相互作用对胆固醇输出和炎症细胞因子产生的影响，并表征相关的细胞机制。我们还建议使用动脉粥样硬化易感小鼠模型来确定 ABCA1 的抗炎和胆固醇输出功能如何导致整个动物的动脉粥样硬化。这些信息将确定这些通路可能受损的部位，这些部位可能与临床相关，并揭示预防 CVD 治疗干预的潜在目标。公共健康相关性：HDL 通过去除动脉细胞中阻碍动脉的胆固醇并抑制炎症来预防心脏病。一种名为 ABCA1 的细胞蛋白可以执行这两种心脏保护功能。这项研究将调查 ABCA1 清除胆固醇和抗炎作用所涉及的细胞途径，并确定这些途径是否可以预防动物患心脏病。