2. Academic Validation
  3. Endothelial Intracellular ANG (Angiogenin) Protects Against Atherosclerosis by Decreasing Endoplasmic Reticulum Stress

Endothelial Intracellular ANG (Angiogenin) Protects Against Atherosclerosis by Decreasing Endoplasmic Reticulum Stress

  • Arterioscler Thromb Vasc Biol. 2022 Mar;42(3):305-325. doi: 10.1161/ATVBAHA.121.317339.
Enyong Su  # 1,  Peng Yu  # 2,  Baoli Zhang  # 1,  Anjing Zhang 3,  Shiyao Xie 1,  Chunyu Zhang 1,  Su Li 1,  Yunzeng Zou 1,  Ming Liu 4,  Hong Jiang 1,  Junbo Ge 1
Affiliations

Affiliations

  • 1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases (E.S., B.Z., S.X., C.Z., S.L., Y.Z., H.J., J.G.), Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Department of Endocrinology and Metabolism (P.Y.), Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Neurorehabilitation Medicine, Kongjiang Branch, the First Rehabilitation Hospital of Shanghai, China (A.Z.).
  • 4 Department of Health Management Center (M.L.), Zhongshan Hospital, Fudan University, Shanghai, China.
  • # Contributed equally.
PMID: 35045729 DOI: 10.1161/ATVBAHA.121.317339
Abstract

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.

Keywords

ST3GAL5; angiogenin; atherosclerosis; endoplasmic reticulum stress; endothelial cell.

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