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

• 批准号: 8217251
• 负责人: RENEE C LEBOEUF
• 金额: $ 41.09万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/8217251
• 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; receptor; reverse cholesterol transport; therapeutic target; transcription factor

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。动脉巨噬细胞中胆固醇的积聚和动脉壁的炎症都是导致 心血管疾病的发展。血浆高密度脂蛋白(HDL)水平与 心血管风险，意味着与高密度脂蛋白代谢相关的因素具有心脏保护作用。高密度脂蛋白保护 通过几种从动脉细胞中去除胆固醇和抑制炎症的机制来对抗心血管疾病。一个 与高密度脂蛋白代谢相关的主要心脏保护因子是ATP结合盒转运体A1(ABCA1)，一种 细胞膜蛋白，将胆固醇和磷脂从细胞输出到去脂的高密度脂蛋白， 例如apoA-I。我们发现ABCA1也通过激活发挥抗炎信号受体的作用 JAK2/STAT3通路，该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的心脏保护作用和 抑制炎症。这些观察表明ABCA1是一个有吸引力的治疗靶点。 导致心血管疾病的两个主要潜在机制。这个项目的目标是确定细胞 ABCA1参与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、生化和质谱学技术 载脂蛋白-ABCA1相互作用对胆固醇输出和炎性细胞因子的影响 并对所涉及的细胞机制进行表征。我们还建议使用易患动脉粥样硬化的 小鼠模型以确定ABCA1的这些抗炎和胆固醇输出功能如何有助于 整个动物的动脉粥样硬化。该信息将定义这些通路的可能损伤位置 可能是临床相关的，并发现了预防心血管疾病的治疗干预的潜在靶点。