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

描述(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。动脉巨噬细胞中胆固醇的积聚和动脉壁的炎症都导致了心血管疾病的发生。血浆高密度(HDL)水平与心血管风险之间存在负相关关系，这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。高密度脂蛋白通过几种机制来预防心血管疾病，这些机制可以从动脉细胞中去除胆固醇，抑制炎症。与高密度脂蛋白代谢相关的主要心脏保护因子是三磷酸腺苷结合盒转运体A1(ABCA1)，它是一种细胞膜蛋白，将胆固醇和磷脂从细胞输出到脂质耗竭的高密度脂蛋白，如载脂蛋白A-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，该通路独立于胆固醇输出活性。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。这些观察表明，ABCA1是治疗导致CVD的两个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ABCA1的胆固醇输出和抗炎活性所涉及的细胞过程，并评估它们在体内的心脏保护作用。我们建议使用突变、生化和质谱学技术来评估载脂蛋白-ABCA1相互作用对胆固醇输出和炎性细胞因子产生的影响，并表征相关的细胞机制。我们还建议使用易患动脉粥样硬化的小鼠模型来确定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。这些信息将确定可能与临床相关的这些通路的损伤部位，并揭示预防心血管疾病的治疗干预的潜在靶点。 与公众健康相关：高密度脂蛋白通过从动脉细胞中去除阻塞动脉的胆固醇和抑制炎症来预防心脏病。一种名为ABCA1的细胞蛋白质可以执行这两种心脏保护功能。这项研究将调查参与ABCA1清除胆固醇和抗炎作用的细胞通路，并确定这些通路是否对动物心脏病具有保护作用。

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.