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

动脉粥样硬化性心血管疾病（CVD）是西方国家死亡和发病的最常见原因。 世界胆固醇在动脉巨噬细胞中的积聚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 通过几种机制，从动脉细胞中清除胆固醇和抑制炎症来对抗CVD。一 与HDL代谢相关的主要心脏保护因子是ATP结合盒转运体A1（ABCA 1）， 将胆固醇和磷脂从细胞输出为脂质耗尽的HDL载脂蛋白的细胞膜蛋白， 例如apoA-I。我们发现ABCA 1也是一种抗炎信号受体，通过激活 JAK 2/STAT 3途径，这是独立的胆固醇输出活动。因此，巨噬细胞ABCA 1 提供了胆固醇逆向转运的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，ABCA 1是一个有吸引力的治疗靶点，用于治疗 这是导致CVD的两个主要潜在机制。这个项目的目标是确定细胞 参与胆固醇输出和ABCA 1的抗炎活性的过程，并评估其 体内心脏保护作用。我们建议使用诱变、生物化学和质谱技术 评估载脂蛋白-ABCA 1相互作用对胆固醇输出和炎性细胞因子的影响 生产和表征所涉及的细胞机制。我们还建议使用动脉粥样硬化敏感的 小鼠模型，以确定ABCA 1的这些抗炎和胆固醇输出功能如何有助于 在整个动物中的动脉粥样硬化这些信息将确定这些通路的可能受损部位， 可能具有临床相关性，并揭示了预防CVD的治疗干预的潜在靶点。

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.