Immune Reactants, Cholesterol and Atherosclerosis

免疫反应物、胆固醇和动脉粥样硬化

• 批准号: 6944364
• 负责人: ALLISON B REISS
• 金额: $ 22.74万
• 依托单位: NYU WINTHROP HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944364
• 关键词: atherosclerosis; cholesterol; clinical research; enzyme activity; enzyme induction /repression; genetically modified animals; homeostasis; human subject; immune complex; immune response; immunoregulation; inflammation; laboratory mouse; longitudinal human study; macrophage; membrane transport proteins; mitogen activated protein kinase; molecular pathology; oxidoreductase inhibitor; oxygenases; protein localization; purinergic receptor; receptor expression; rheumatoid arthritis; steroid metabolism; systemic lupus erythematosus; tissue /cell culture

DESCRIPTION (provided by applicant): Recognition of the factors associated with maintaining cholesterol balance may illuminate the pathological mechanisms involved in diseases caused by cholesterol excess, with atherosclerosis the leading example. Homeostatic mechanisms that orchestrate cholesterol balance in the vessel wall and defend against atherosclerosis involve reverse cholesterol transport (RCT) from arterial wall to liver. A central mediator of RCT is the enzyme cholesterol 27-hydroxylase (27-OHase). 27-OHase both facilitates cholesterol transport to the liver and, by generating oxysterol signaling molecules, promotes expression of other RCT proteins, specifically ATP binding cassette transporter 1 (ABCA1). Inflammation is an integral feature of atherosclerosis. The autoimmune disorders systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are characterized by high levels of circulating immune reactants and increased risk of atherosclerosis. We have shown that immune reactants affect cellular cholesterol flux by markedly decreasing 27-OHase and ABCA1 expression. We postulate that, in patients with autoimmune disorders, disruption of cholesterol homeostasis by immune reactants leads to accelerated atherosclerosis. To better understand the immunological mechanisms underlying development of atherosclerosis and to begin to counteract the atherogenic consequences, we propose 4 aims: 1) effect of over- and under- expression of 27-OHase on receptors and transport proteins involved in cholesterol flux, with the addition of a pathophysiologic correlate of atherogenesis: quantitation of foam cell transformation of THP-1 macrophages under the various conditions described; 2) immunomodulatory effects of serum from SLE and RA patients on these cholesterol transport/receptor proteins; 3) mechanisms of up regulation of 27-OHase via adenosine receptor agonists and consequent effects on cholesterol trafficking and 4) therapeutic intervention (statins, adenosine agonists) on cholesterol transport/receptor protein gene expression in a murine model (apolipoprotein E knockout mouse).

描述（由申请人提供）：对与维持胆固醇平衡相关的因素的认识可以阐明胆固醇过量引起的疾病的病理机制，其中动脉粥样硬化就是主要例子。协调血管壁胆固醇平衡和预防动脉粥样硬化的稳态机制涉及从动脉壁到肝脏的反向胆固醇转运（RCT）。 RCT 的核心介质是胆固醇 27-羟化酶 (27-OHase)。 27-OHase 既促进胆固醇转运至肝脏，又通过产生氧甾醇信号分子促进其他 RCT 蛋白的表达，特别是 ATP 结合盒转运蛋白 1 (ABCA1)。炎症是动脉粥样硬化的一个重要特征。自身免疫性疾病系统性红斑狼疮 (SLE) 和类风湿关节炎 (RA) 的特点是循环免疫反应物水平高和动脉粥样硬化风险增加。我们已经证明，免疫反应物通过显着降低 27-OHase 和 ABCA1 表达来影响细胞胆固醇通量。我们假设，在患有自身免疫性疾病的患者中，免疫反应物破坏胆固醇稳态会导致动脉粥样硬化加速。为了更好地了解动脉粥样硬化发展的免疫学机制并开始抵消致动脉粥样硬化的后果，我们提出了 4 个目标：1) 27-OHase 过度表达和表达不足对参与胆固醇流动的受体和转运蛋白的影响，其中添加动脉粥样硬化形成的病理生理学相关性：在所述的各种条件下对 THP-1 巨噬细胞的泡沫细胞转化进行定量； 2) SLE和RA患者血清对这些胆固醇转运/受体蛋白的免疫调节作用； 3) 通过腺苷受体激动剂上调 27-OHase 的机制及其对胆固醇运输的影响，以及 4) 对小鼠模型（载脂蛋白 E 敲除小鼠）中胆固醇转运/受体蛋白基因表达的治疗干预（他汀类药物、腺苷激动剂）。