Role of scavenger receptors in atherogenesis and development of new therapeutic methods

清道夫受体在动脉粥样硬化形成中的作用和新治疗方法的开发

• 批准号: 12557023
• 负责人: TAKEYA Motohiro
• 金额: $ 8.38万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12557023/
• 关键词: atherosclerosis; scavenger receptors; SR-AI,II; LOX-1; anti-oxidant; knockout mice; foam cell formation; alpha-1-antitrypsin; スカベンジャー受容体ファミリー; SR-AI, II(CD204); LOX-1(Lectin-like oxidized LDL receptor-1); ビタミンE; SR-AI, II; マクロファージ; α1-antitr

Scavenger receptors (SRs) are a family of cell surface glycoproteins able to bind modified LDLs such as acetyiated LDL and oxidized LDL. Currently, SR family molecules are classified into six groups, namely class A to class F. Class A SR type I and type II(SR-AI,II) was the first SR to be cloned. In our previous study, SR-A I,II deficiency induced 60 % reduction of atherosclerotic lesions in atherpgenic ApoE-deficient mice of crossbred strains. To exdude the influence of crossbreeding, a new study using inbred C57BL/6J mice has been performed in me present project After 7 months of high fat diet, 70% reduction of lesion size was observed inSR-A I,II deficient C57BL/6J mice. On the other hand, administration of BO-653, a new antioxidant, has induced 75% size reduction in normal C57BL/6J mice. This fact indicated that anti-oxidant therapy is similarly or more effective in reducing atherogenesis compared to SR-AI,II deficiency.To explore the effect of other types of SRs, we have studies the lesion development using a mouse strain that is deficient in a class E scavenger receptor, LOX-1 (lectin-like oxidized LDL receptor-1). So far, however, no significant difference in lesion size has been observed yet.Concerning the study of LDL modification, we have found the complex formation of LDL and alpha-1-antitrypsin (AT) in human plasma. AT-LDL complex was found to be up taken by macrophages four times more rapidly than LDL. Since actual deposition of AT-LDL complex in human atherosclerotic lesion has been observed, suppression of AT-LDL formation and its deposition may reduce the development of atherosclerotic lesions.

清道夫受体（SRs）是一类细胞表面糖蛋白，能够结合修饰的LDL，如乙酰化LDL和氧化LDL。目前，将SR家族分子分为A类至f类6类，A类SR I型和II型（SR- ai，II）是第一个克隆的SR。在我们之前的研究中，SR-A I，II缺乏诱导杂交品系的致动脉粥样硬化病变减少60%。为了消除杂交的影响，本项目使用近交系C57BL/6J小鼠进行了一项新的研究，在高脂饮食7个月后，观察到inSR-A I，II缺陷C57BL/6J小鼠的病变大小减少了70%。另一方面，给药BO-653（一种新型抗氧化剂）可使正常C57BL/6J小鼠的体积减小75%。这一事实表明，与缺乏SR-AI，II相比，抗氧化治疗在减少动脉粥样硬化方面类似或更有效。为了探索其他类型的SRs的影响，我们使用缺乏E类清除率受体LOX-1（凝集素样氧化LDL受体-1）的小鼠品系研究了病变的发展。然而，到目前为止，尚未观察到病变大小的显著差异。关于LDL修饰的研究，我们发现LDL与α -1-抗胰蛋白酶（AT）在人血浆中形成复合物。巨噬细胞吸收AT-LDL复合物的速度是LDL的4倍。由于已经观察到AT-LDL复合物在人类动脉粥样硬化病变中的实际沉积，抑制AT-LDL的形成及其沉积可能会减少动脉粥样硬化病变的发展。

项目成果

Sakashita N, Miyazaki A, Takeya M, Horiuchi S, Chang CCY, Chang TY, Takahashi K.: "Localization of Human Acyl-Coenzyme A:Cholesterol Acyltransferase-1 (ACAT-1) in Macrophages and in Various Tissues."Am J Pathol.. 156. 227-236 (2000)

Sakashita N、Miyazaki A、Takeya M、Horiuchi S、Chang CCY、Chang TY、Takahashi K.：“人酰基辅酶 A：胆固醇酰基转移酶-1 (ACAT-1) 在巨噬细胞和各种组织中的定位。”Am J

Takeya M, Tomokiyo R, Jinnouchi K, Honda M, Wada Y, Suzuki H, Kodama T, Takahashi K.: "Leucocyte Typing VII, White Cell Differentiation Anltgens (Mason D et al. eds), Oxford University Press"CD204 : Macrophage scavenger receptor, a new differentiation mar

Takeya M、Tomokiyo R、Jinnouchi K、Honda M、Wada Y、Suzuki H、Kodama T、Takahashi K.：“白细胞分型 VII，白细胞分化 Anltgens（Mason D 等编辑），牛津大学出版社”CD204：巨噬细胞

Takeya M et al.: "Macrophage scavenger receptor, a new differentiation marker for macrophages"In Leucocyte Typing VII, White Cell Differentiation Antigens. (in press). (2002)

Takeya M 等人：“巨噬细胞清道夫受体，巨噬细胞的新分化标记”，《白细胞分型 VII》，白细胞分化抗原。

高橋 潔, 内藤眞, 竹屋元裕: "生命を支えるマクロファージ"文光堂(東京). 542 (2001)

Kiyoshi Takahashi、Makoto Naito、Motohiro Takeya：“支持生命的巨噬细胞”Bunkodo（东京）542（2001）。

Takeya M et al.: "Macrophage scavenger receptor, a new differentiation marker for macrophages."In Leucocyte Typing VII, White Cell Differentiation Anitgens (Mason D et al.eds), Oxford University Press. (in press). (2001)

Takeya M 等人：“巨噬细胞清道夫受体，一种新的巨噬细胞分化标记。”《白细胞分型 VII》，白细胞分化抗原（Mason D 等人编辑），牛津大学出版社。