血管生长素
内质网
内皮细胞活化
未折叠蛋白反应
内皮功能障碍
载脂蛋白E
内分泌学
内皮
下调和上调
内科学
内皮干细胞
单核细胞
生物
细胞生物学
化学
作者
Enyong Su,Peng Yu,Baoli Zhang,Anjing Zhang,Shiyao Xie,Chunyu Zhang,Su Li,Yunzeng Zou,Ming Liu,Hong Jiang,Juying Qian
标识
DOI:10.1161/atvbaha.121.317339
摘要
Background: ANG (angiogenin) is essential for cellular adaptation to endoplasmic reticulum (ER) stress, a process closely associated with cardiovascular diseases, including atherosclerosis. We aimed to investigate the role of ANG in the progression of atherosclerosis and elucidate its underlying molecular mechanisms. Methods: We constructed adenoassociated virus 9 ANG overexpression vectors and endothelial ANG- and ApoE (apolipoprotein E)-deficient mice to determine the effects of ANG on ER stress and atherosclerotic lesions. RNA sequencing of endothelial ANG- and ApoE-deficient mice identified ANG-dependent downregulation of ST3GAL5 (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) expression, and the direct regulation of ST3GAL5 by ANG was verified by chromatin immunoprecipitation sequencing and luciferase reporter assay results. Results: Reanalysis of expression profiling datasets indicated decreased ANG levels in patients’ atherosclerotic lesions, and these data were validated in aortas from ApoE − /− mice. ER stress marker and adhesion molecule levels, aortic root lesions and macrophage deposition were substantially reduced in ApoE −/− mice injected with an adenoassociated virus 9 ANG without signal peptide (ANG-ΔSP) overexpression vector compared with empty and full-length ANG overexpression vectors. Endothelial ANG deficiency significantly elevated ER stress and increased adhesion molecule expression, which aggravated atherosclerotic lesions and enhanced THP-1 monocyte adhesion to endothelial cells in vivo and in vitro, respectively. Furthermore, ANG-ΔSP overexpression significantly attenuated oxidized low-density lipoprotein-induced ER stress and THP-1 monocyte adhesion to endothelial cells, which were reversed by ST3GAL5 inhibition. Conclusions: These results suggest that endothelial intracellular ANG is a novel therapeutic against atherosclerosis and exerts atheroprotective effects via ST3GAL5-mediated ER stress suppression.
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