LOCALLY PRODUCED APOLIPOPROTEIN E IN ATHEROSCLEROSIS

局部产生的载脂蛋白 E 在动脉粥样硬化中的作用

• 批准号: 2031150
• 负责人: WILLIAM A BOISVERT
• 金额: $ 10.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2031150
• 关键词: T lymphocyte; apolipoprotein E; atherosclerosis; bone marrow transplantation; cholesterol; disease /disorder etiology; gene targeting; high density lipoproteins; laboratory mouse; low density lipoprotein; macrophage; pathologic process; phenotype

DESCRIPTION (Adapted from Investigator's Abstract): Although apoE is expressed abundantly in atherosclerotic lesions by the resident macrophages, the specific function of this protein in the lesion environment and its effect on atherogenesis have not been identified. To address the role of apoE specifically in lesions, a phenotype of wild-type mice in which apoE was essentially eliminated from the lesion was developed. This was done by transplanting irradiated mice with bone marrow from apoE-/- mice, which resulted in repopulation of these mice with macrophages (M) that did not express apoE in lesions. A significant reduction in diet-induced atherosclerosis was observed in these mice compared to similarly treated mice with normal M , despite similar circulating levels of lipids and apoE. This is strongly suggests that apoE in lesions is produced locally by the M , and provides compelling evidence that lesion apoE promotes atherosclerosis. Because the mechanisms responsible for the observed proatherogenic role of lesion apoE are known, this proposal addresses several possible mechanisms in the first 3 Specific Aims, and probes an alternative explanation underlying the above observation in the fourth aim. This first aim will test the hypothesis that lesion apoE promotes atherosclerosis by retaining atherogenic lipoproteins to favor foam cell formation. This will be tested by generating LDL-R/-mice with and without apoE in their lesions, and comparing the extent of atherosclerosis and lipid accumulation in the vascular walls. The second Aim will determine if apoE is necessary for facilitating cholesterol efflux out of the lesion. Contrary to popular belief that apoE facilitates HDL-mediated cholesterol efflux, the proatherogenic role of apoE suggests that it may not be essential for cholesterol efflux from lesions. This hypothesis will be tested in LDL-R-/- mice and LDL-R-/-, apoAI-/- double knockout mice by generating four phenotypes with and without lesion apoE and/or HDL. Because apoE has been shown to inhibit T cell function, the third Aim will test if lesion apoE exerts it proatherogenic effect by altering T cell functions considered to be atheroprotective. The fourth Aim will examine the possibility that the reduction in atherosclerosis of the mice transplanted with apoE-/- bone marrow was not necessarily due to the absence of apoE in the lesion, but was due to atheroprotection offered by transfer of resident bone marrow memory cells sensitized to certain antigens circulating in the hyperlipidemic apoE-/- mice. Identification of the role of apoE in lesions may lead to interventions aimed at preventing atherosclerosis.

描述（改编自研究者摘要）：虽然 apoE 是 常驻巨噬细胞在动脉粥样硬化病变中大量表达， 该蛋白在病变环境中的具体功能及其 对动脉粥样硬化形成的影响尚未确定。 为了解决的角色 apoE 特别出现在病变中，这是野生型小鼠的一种表型，其中 apoE 基本上从病灶中消除了。 这是由 将 apoE-/- 小鼠的骨髓移植到受辐射的小鼠中， 导致这些小鼠体内的巨噬细胞（M）重新繁殖，而巨噬细胞并没有 病灶中表达 apoE。 饮食引起的显着减少 与接受类似治疗的小鼠相比，在这些小鼠中观察到动脉粥样硬化 尽管脂质和 apoE 的循环水平相似，但 M 值正常的小鼠。 这强烈表明病变中的 apoE 是由 M 局部产生的。 ，并提供了令人信服的证据表明 apoE 促进了病变 动脉粥样硬化。 因为负责观察到的机制 病变 apoE 的促动脉粥样硬化作用是已知的，该提案解决了 前 3 个具体目标中的几种可能机制，并探讨了 第四个目标中上述观察结果的替代解释。 第一个目标将检验 apoE 促进病变的假设 通过保留致动脉粥样化脂蛋白以有利于泡沫细胞来预防动脉粥样硬化 形成。 这将通过生成 LDL-R/-小鼠进行测试，无论是否使用 病变中的apoE，并比较动脉粥样硬化和血脂的程度 积聚于血管壁。 第二个目标将确定 apoE 是否 对于促进胆固醇从病变处流出是必要的。 与 apoE 促进 HDL 介导的胆固醇这一普遍观点相反 流出，apoE 的促动脉粥样硬化作用表明它可能不是 对于胆固醇从病变中流出至关重要。 这个假设将是 在 LDL-R-/- 小鼠和 LDL-R-/-、apoAI-/- 双敲除小鼠中进行测试 产生有和没有损伤 apoE 和/或 HDL 的四种表型。 因为 apoE 已被证明可以抑制 T 细胞功能，第三个目标将测试是否 病变 apoE 通过改变 T 细胞功能发挥促动脉粥样硬化作用 被认为具有动脉粥样硬化保护作用。 第四个目标将审查 移植小鼠的动脉粥样硬化减少的可能性 具有 apoE-/- 骨髓并不一定是由于 apoE 的缺失 病变，但由于居民转移提供的动脉粥样硬化保护 骨髓记忆细胞对循环中的某些抗原敏感 高脂血症apoE-/-小鼠。 鉴定 apoE 在病变中的作用 可能导致旨在预防动脉粥样硬化的干预措施。