Cheng Wenzhuo, Shu Meng, Kuang Liwen, Bai Xiangli, Jia Xiong, Zhao Ying, Lu Yajing, Zhu Lin, Wang Li, Zhu Yan, Shu Yan, Song Yi, Jin Si
Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Department of Pediatrics, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Int J Biol Macromol. 2023 Apr 30;235:123836. doi: 10.1016/j.ijbiomac.2023.123836. Epub 2023 Feb 25.
Glycated low-density lipoprotein (G-LDL) is an established proatherosclerotic factor, but the mechanism is not completely understood. In vitro, we evaluated the uptake and transcytosis rates of N-LDL and G-LDL in endothelial cells and the uptake and transcytosis rates of G-LDL were much higher than those of N-LDL. Then, using small interfering RNAs, the receptor mediating G-LDL uptake and transcytosis was screened among eight candidate receptors, and the mechanism of the receptor regulation was thoroughly examined. We discovered that scavenger receptor A (SR-A) knockdown dramatically decreased the uptake and transcytosis rates of G-LDL. Additionally, endothelial cells with overexpressed SR-A had enhanced G-LDL uptake and transcytosis. In vivo, G-LDL was injected in the tail vein of ApoE mice to investigate whether G-LDL affects atherosclerotic plaque formation. Compared with the injection of N-LDL, the injection of G-LDL accelerated atherosclerotic plaque formation in ApoE mice, which was ameliorated by endothelial cells specific SR-A knockdown. Together, our results provide the first demonstration that the transcytosis of G-LDL across endothelial cells is much faster than that of N-LDL and SR-A is the major type of receptor responsible for G-LDL binding and transcytosis across endothelial cells.
糖化低密度脂蛋白（G-LDL）是一种已确定的促动脉粥样硬化因子，但其机制尚未完全明确。在体外实验中，我们评估了内皮细胞中天然低密度脂蛋白（N-LDL）和糖化低密度脂蛋白（G-LDL）的摄取和转胞吞率，结果显示G-LDL的摄取和转胞吞率远高于N-LDL。随后，我们利用小干扰RNA在8种候选受体中筛选介导G-LDL摄取和转胞吞的受体，并深入研究该受体的调控机制。我们发现，敲低清道夫受体A（SR-A）可显著降低G-LDL的摄取和转胞吞率。此外，过表达SR-A的内皮细胞对G-LDL的摄取和转胞吞能力增强。在体内实验中，我们通过尾静脉注射G-LDL至载脂蛋白E（ApoE）基因敲除小鼠体内，以研究G-LDL是否影响动脉粥样硬化斑块的形成。与注射N-LDL相比，注射G-LDL加速了ApoE小鼠动脉粥样硬化斑块的形成，而内皮细胞特异性敲低SR-A可改善这一现象。综上所述，我们的研究首次证实，G-LDL在内皮细胞中的转胞吞速度远快于N-LDL，且SR-A是介导G-LDL在内皮细胞上结合与转胞吞的主要受体类型。
