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

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有助于心血管疾病的发展。血浆高密度脂蛋白（HDL）水平与心血管风险呈负相关，这意味着与HDL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防止心血管疾病，从动脉细胞中去除胆固醇并抑制炎症。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)，这是一种细胞膜蛋白，可将胆固醇和磷脂从细胞输出到脂质耗尽的HDL载脂蛋白，如apoa - 1。我们发现ABCA1还通过激活JAK2/STAT3通路作为抗炎信号受体，该通路独立于胆固醇输出活性。因此，巨噬细胞ABCA1在逆向胆固醇转运和抑制炎症的心脏保护作用之间提供了直接的生化联系。这些观察结果表明，ABCA1是治疗导致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胆固醇输出和ABCA1抗炎活性的细胞过程，并评估其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，并表征所涉及的细胞机制。我们还建议使用动脉粥样硬化易感小鼠模型来确定ABCA1的这些抗炎和胆固醇输出功能如何在整个动物中促进动脉粥样硬化。这一信息将确定这些通路受损的可能位点，这些位点可能与临床相关，并揭示预防心血管疾病的治疗干预的潜在靶点。

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.