The mechanism for Se-afforded protection against athero*

硒提供的预防动脉粥样硬化的机制*

• 批准号: 6524841
• 负责人: Fong-Fong Chu
• 金额: $ 7.5万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524841
• 关键词: antiatherogenic agent; antioxidants; atherosclerosis; blood chemistry; cardiovascular disorder prevention; chemical structure function; cytoprotection; dietary control; dietary trace element; enzyme induction /repression; enzyme linked immunosorbent assay; gene targeting; genetically modified animals; glutathione peroxidase; human subject; inflammation; isozymes; laboratory mouse; lipids; low density lipoprotein; mutant; nuclear factor kappa beta; nutrition related tag; oxidation; pathologic process; selenium; tissue /cell culture

DESCRIPTION (provided by applicant) The long-term objective is to understand the mechanism for the antioxidant effect of selenium against inflammation. Low Se content is associated with a higher incidence of cardiovascular diseases. The pathogenesis of atherosclerosis is recognized as a chronic inflammatory disease in endothelium, and inflammation in other organs may also increase the risk of atherogenesis. The investigators have recently found that mice deficient in two Se-dependent glutathione peroxidase (GPX) isozymes, GPX-1 and GPX-GI (encoded by Gpxl and Gpx2) develop severe colitis by the time they are weaned. Because GPX isozymes have been implicated to be the anti-atherosclerotic activity of Se, the investigators propose that the GPX-1 and GPX-GI protect against atherosclerotic lesions. In the first aim, the investigators plan to determine if GPX-1 and GPX-GI are the major anti-atherosclerotic activity of Se. They will study if mice deficient in either the Gpxl or the Gpx2 gene, or both genes, in C57BW6J background have more severe atherosclerotic lesions than the control mice. If these mice deficient in one or both of GPX isozymes no longer respond to dietary Se modulation, this suggests that the GPX isozyrnes are the major Se-dependent anti-atherosclerotic activity. If one or both GPX-1 and GPX-GI have anti-atherosclerotic activity, the investigators will distinguish this activity in the prevention of low density lipoprotein (LDL) oxidation originated from dietary and endogenous sources in the second aim. If Gpx2-knockout mice have a higher level of oxidized LDL in the plasma than control mice after being fed a high fat diet, because the Gpx2 gene is highly expressed in the intestinal epithelium, this suggests that the LDL oxidation may occur from the dietary source. If Gpxl-knockout monocytes or neutrophils can generate more oxidized LDL than control cells, this suggests that GPX-1 can prevent LDL oxidation from endogenous cells. Whether GPX-1 inhibits NF-KB activation, which plays a pivotal role in inflammatory response, will be analyzed in macrophages/monocytes. If neither GPX-1 nor GPX-GI has anti-atherosclerotic activity, or these 2 isozymes are not the major Se-dependent anti-atherosclerotic activity, it suggests other selenoproteins contribute. The investigators will generate GpxS-knockout mice deficient in the plasma GPX isozyme, GPX-P, to study this activity as they have done for Gpx2-knockout mice.

描述（由申请人提供） 长期目标是了解抗氧化剂的机制 硒反对炎症的影响。 低SE含量与 心血管疾病的发病率更高。 发病机理 动脉粥样硬化被认为​​是一种慢性炎症性疾病 内皮以及其他器官的炎症也可能增加 动脉粥样硬化。 调查人员最近发现小鼠缺乏 两个SE依赖性谷胱甘肽过氧化物酶（GPX）同工酶，GPX-1和GPX-GI （由GPXL和GPX2编码）在断奶时会发展出严重的结肠炎。 因为GPX同工酶已被牵涉到抗动脉粥样硬化 SE的活动，研究人员建议GPX-1和GPX-GI保护 针对动脉粥样硬化病变。 在第一个目的中，调查人员计划确定GPX-1和GPX-GI是否是 SE的主要抗动物性活性。 他们会学习小鼠 C57BW6J中的GPXL或GPX2基因或两个基因缺乏 背景比对照小鼠具有更严重的动脉粥样硬化病变。 如果 这些小鼠缺乏一只或两只GPX同工酶不再响应 饮食SE调节，这表明GPX等二氏菌是主要的 SE依赖性抗动脉粥样硬化活性。 如果一个或两个GPX-1和GPX-GI具有抗动脉粥样硬化活性，则 研究人员将在预防低密度方面区分这一活动 脂蛋白（LDL）氧化起源于饮食和内源性来源 第二个目标。 如果GPX2敲除小鼠的氧化LDL水平较高 喂养高脂肪饮食后的血浆比对照小鼠，因为GPX2 基因在肠上皮中高度表达，这表明 LDL氧化可能来自饮食来源。 如果GPXL-敲除单核细胞 或中性粒细胞比对照细胞产生更多的氧化LDL，这 表明GPX-1可以防止内源细胞的LDL氧化。无论 GPX-1抑制NF-KB激活，该激活在炎症中起关键作用 反应将在巨噬细胞/单核细胞中进行分析。 如果GPX-1和GPX-GI都没有抗动脉粥样硬化活性，或者这2 同工酶不是主要的SE依赖性抗动物性活性，而是 建议其他硒蛋白会贡献。 调查人员将产生 GPXS-KNOCKOUT小鼠缺乏等离子体GPX同工酶GPX-P，研究这一点 与GPX2敲除小鼠所做的活动一样。