Sano H, Nagai R, Matsumoto K, Horiuchi S
Department of Biochemistry, Kumamoto University School of Medicine, Japan.
Mech Ageing Dev. 1999 Mar 15;107(3):333-46. doi: 10.1016/s0047-6374(99)00011-1.
Long-term incubation of proteins with glucose leads, through the formation of early stage products such as Schiff base and Amadori rearrangement products, to the formation of advanced glycation end products (AGE). Recent studies of AGE-structures as well as the receptor for AGE-proteins (AGE-receptors) have emphasized the involvement of protein modification by AGE in aging and age-enhanced disease processes. Immunohistochemical analyses of human atherosclerotic lesions using a monoclonal anti-AGE antibody have demonstrated diffuse extracellular AGE-deposition as well as dense intracellular AGE-deposition in macrophage- and vascular smooth muscle cell (SMC)-derived foam cells. In vitro experiments using both CHO cells overexpressing macrophage scavenger receptor-A (MSR-A) and peritoneal macrophages from MSR-A-knockout mice have shown that the MSR-A plays a major role in endocytic uptake of AGE-proteins by macrophages. Furthermore, in vitro experiments with rabbit arterial SMCs demonstrated a novel AGE-receptor mediating endocytosis of AGE-proteins. These in vivo and in vitro experiments suggest that AGE-proteins formed extracellularly in atherosclerotic lesions are endocytosed by macrophages through MSR-A in the early stage, and by SMCs through the novel AGE-receptor in the advanced stage, implicating functional contribution of the AGE-receptor-mediated interaction of AGE-proteins with these cells to atherosclerotic processes in arterial walls.
蛋白质与葡萄糖的长期孵育会通过席夫碱和阿马多里重排产物等早期产物的形成，导致晚期糖基化终产物（AGE）的形成。最近对AGE结构以及AGE蛋白受体（AGE受体）的研究强调了AGE对蛋白质的修饰在衰老和与年龄相关的疾病进程中的作用。使用单克隆抗AGE抗体对人类动脉粥样硬化病变进行的免疫组织化学分析表明，在巨噬细胞和血管平滑肌细胞（SMC）来源的泡沫细胞中存在弥漫性细胞外AGE沉积以及密集的细胞内AGE沉积。使用过表达巨噬细胞清道夫受体-A（MSR-A）的CHO细胞和来自MSR-A基因敲除小鼠的腹膜巨噬细胞进行的体外实验表明，MSR-A在巨噬细胞对AGE蛋白的内吞摄取中起主要作用。此外，用兔动脉SMC进行的体外实验证明了一种介导AGE蛋白内吞作用的新型AGE受体。这些体内和体外实验表明，动脉粥样硬化病变中细胞外形成的AGE蛋白在早期被巨噬细胞通过MSR-A内吞，在晚期被SMC通过新型AGE受体内吞，这意味着AGE受体介导的AGE蛋白与这些细胞的相互作用对动脉壁的动脉粥样硬化进程有功能性贡献。
