Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4.
Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4.
复制标题
作者：
Arakawa M;Mita T;Azuma K;Ebato C;Goto H;Nomiyama T;Fujitani Y;Hirose T;Kawamori R;Watada H
外源性施用胰高血糖素样肽-1（GLP-1）或GLP-1受体激动剂如毒蜥外泌肽-4对心血管系统具有直接的有益作用。然而，它们对动脉粥样硬化形成的影响尚未阐明。本研究的目的是研究GLP-1对血管壁上单核细胞/巨噬细胞积聚的影响，这是动脉粥样硬化形成的最早步骤之一。在C57 BL/6或载脂蛋白E缺陷小鼠（apoE−/−）中连续输注低剂量（300 pmol ·kg − 1·day −1）或高剂量（24 nmol · kg−1 · day−1）exendin-4后，我们评价了单核细胞与胸主动脉内皮细胞的粘附和主动脉瓣周围的动脉病变。在小鼠巨噬细胞和人单核细胞中研究了exendin-4的作用。用毒蜥外泌肽-4处理显著抑制C57 BL/6小鼠的睾丸中的单核细胞粘附，而不影响代谢参数。在apoE−/−小鼠中，相同的治疗减少了单核细胞与内皮细胞的粘附并抑制了动脉粥样硬化形成。在体外用exendin-4处理小鼠巨噬细胞抑制了脂多糖诱导的肿瘤坏死因子-α和单核细胞趋化蛋白-1的mRNA表达，并抑制了核因子-κB组分p65的核转位。这种作用可被cAMP抑制剂MDL-12330 A或蛋白激酶A特异性抑制剂PKI 14 -22逆转。在人单核细胞中，exendin-4降低了CD 11b的表达。我们的数据表明，GLP-1受体激动剂通过抑制巨噬细胞中的炎症反应，减少了单核细胞/巨噬细胞在动脉壁中的积聚，这种作用可能有助于通过exendin-4减轻动脉粥样硬化病变。
Exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonists such as an exendin-4 has direct beneficial effects on the cardiovascular system. However, their effects on atherosclerogenesis have not been elucidated. The aim of this study was to investigate the effects of GLP-1 on accumulation of monocytes/macrophages on the vascular wall, one of the earliest steps in atherosclerogenesis. After continuous infusion of low (300 pmol · kg−1 · day−1) or high (24 nmol · kg−1 · day−1) dose of exendin-4 in C57BL/6 or apolipoprotein E–deficient mice (apoE−/−), we evaluated monocyte adhesion to the endothelia of thoracic aorta and arteriosclerotic lesions around the aortic valve. The effects of exendin-4 were investigated in mouse macrophages and human monocytes. Treatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE−/− mice, the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor-α and monocyte chemoattractant protein-1, and suppressed nuclear translocation of p65, a component of nuclear factor-κB. This effect was reversed by either MDL-12330A, a cAMP inhibitor or PKI14-22, a protein kinase A–specific inhibitor. In human monocytes, exendin-4 reduced the expression of CD11b. Our data suggested that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages, and that this effect may contribute to the attenuation of atherosclerotic lesion by exendin-4.