Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice.
Native incretins prevent the development of atherosclerotic lesions in apolipoprotein E knockout mice.
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DOI：
10.1007/s00125-011-2241-2
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发表时间：
2011-10
期刊：
影响因子：
8.2
通讯作者：
Hirano, T.
中科院分区：
文献类型：
--
作者：
Nagashima, M.;Watanabe, T.;Terasaki, M.;Tomoyasu, M.;Nohtomi, K.;Kim-Kaneyama, J.;Miyazaki, A.;Hirano, T.
关键词：
多项证据表明，基于肠促胰岛素的疗法可抑制 2 型糖尿病患者心血管疾病的发展。我们研究了胰高血糖素样肽-1 (GLP-1) 和葡萄糖依赖性促胰岛素多肽 (GIP) 可以预防 Apoe −/− 小鼠动脉粥样硬化发展的可能性。 Apoe −/− 小鼠（17 周龄）接受 GLP-1(7–36) 酰胺、GLP-1(9–36) 酰胺、GIP(1–42) 或 GIP(3–42) 治疗 4 周。测定主动脉粥样硬化、氧化低密度脂蛋白诱导的泡沫细胞形成以及渗出液腹膜巨噬细胞中的相关基因表达。与载体对照相比，GLP-1(7-36)酰胺或GIP(1-42)的施用显着抑制主动脉壁中的动脉粥样硬化病变和巨噬细胞浸润。通过与 GLP-1 和 GIP 受体的特异性拮抗剂（即 exendin(9-39) 或 Pro3(GIP)）共同输注可消除这些效应。 GLP-1(7-36)酰胺和GIP(1-42)的抗动脉粥样硬化作用与巨噬细胞中泡沫细胞形成的显着减少以及CD36和酰基辅酶A：胆固醇酰基转移酶-1 (ACAT-1)的下调有关。 GLP-1 和 GIP 受体均在 Apoe −/− 小鼠巨噬细胞中检测到。将巨噬细胞与 GLP-1(7–36)amide 或 GIP(1–42) 离体孵育 48 小时，可显着抑制泡沫细胞的形成。在用 exendin(9−39) 或 (Pro3)GIP 或腺苷酸环化酶抑制剂 MDL12,330A 预处理的巨噬细胞中，这种效应完全消失，并且通过与腺苷酸环化酶激活剂毛喉素一起孵育来模拟。非活性形式 GLP-1(9-36) 酰胺和 GIP(3-42) 对动脉粥样硬化和巨噬细胞泡沫细胞形成没有影响。我们的研究首次证明活性形式的 GLP-1 和 GIP 通过其自身受体抑制巨噬细胞泡沫细胞形成，然后激活 cAMP，从而发挥抗动脉粥样硬化作用。这些作用的分子机制与肠促胰素下调 CD36 和 ACAT-1 有关。本文的在线版本 (doi:10.1007/s00125-011-2241-2) 包含经过同行评审但未经编辑的补充材料，可供授权用户使用。
Several lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes. We investigated the possibility that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can prevent the development of atherosclerosis in Apoe −/− mice. Apoe −/− mice (17 weeks old) were administered GLP-1(7–36)amide, GLP-1(9–36)amide, GIP(1–42) or GIP(3–42) for 4 weeks. Aortic atherosclerosis, oxidised LDL-induced foam cell formation and related gene expression in exudate peritoneal macrophages were determined. Administration of GLP-1(7–36)amide or GIP(1–42) significantly suppressed atherosclerotic lesions and macrophage infiltration in the aortic wall, compared with vehicle controls. These effects were cancelled by co-infusion with specific antagonists for GLP-1 and GIP receptors, namely exendin(9–39) or Pro3(GIP). The anti-atherosclerotic effects of GLP-1(7–36)amide and GIP(1–42) were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) in macrophages. GLP-1 and GIP receptors were both detected in Apoe −/− mouse macrophages. Ex vivo incubation of macrophages with GLP-1(7–36)amide or GIP(1–42) for 48 h significantly suppressed foam cell formation. This effect was wholly abolished in macrophages pretreated with exendin(9−39) or (Pro3)GIP, or with an adenylate cyclase inhibitor, MDL12,330A, and was mimicked by incubation with an adenylate cyclase activator, forskolin. The inactive forms, GLP-1(9–36)amide and GIP(3–42), had no effects on atherosclerosis and macrophage foam cell formation. Our study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins. The online version of this article (doi:10.1007/s00125-011-2241-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
5.3
作者：
Okutsu, Reiko;Yoshikawa, Tomohiro;Yabuuchi, Youichi
通讯作者：
Yabuuchi, Youichi
影响因子：
7.7
作者：
Arakawa M;Mita T;Azuma K;Ebato C;Goto H;Nomiyama T;Fujitani Y;Hirose T;Kawamori R;Watada H
通讯作者：
Watada H
DOI：
10.1152/ajpendo.00237.2004
发表时间：
2004-12-01
影响因子：
5.1
作者：
Nyström, T;Gutniak, MK;Sjöholm, Å
通讯作者：
Sjöholm, Å
影响因子：
3.9
作者：
BOTHAM, KM
通讯作者：
BOTHAM, KM
影响因子：
--
作者：
Hansotia, T;Drucker, DJ
通讯作者：
Drucker, DJ