Scavenger receptor a mediates glycated LDL transcytosis across endothelial cells to promote atherosclerosis

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.