title: PERK-eIF2α-ATF4-CHOP signaling contributes to TNFα-induced vascular calcification.
abstract: BACKGROUND
  Vascular calcification is a common feature in patients with chronic kidney disease (CKD). CKD increases serum levels of tumor necrosis factor-α (TNFα), a critical mediator of vascular calcification. However, the molecular mechanism by which TNFα promotes CKD-dependent vascular calcification remains obscure. The purpose of the present study was to investigate whether TNFα-induced vascular calcification in CKD is caused by the endoplasmic reticulum response involving protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP).
  
  
  RESULTS
  We examined the effects of TNFα on the endoplasmic reticulum (ER) stress response of vascular smooth muscle cells (VSMCs). TNFα treatment drastically induced the PERK-eIF2α-ATF4-CHOP axis of the ER stress response in VSMCs. PERK, ATF4, and CHOP shRNA-mediated knockdowns drastically inhibited mineralization and osteogenesis of VSMCs induced by TNFα. CKD induced by 5/6 nephrectomies activated the PERK-eIF2α-ATF4-CHOP axis of the ER stress response in the aortas of ApoE-/- mice with increased aortic TNFα expression and vascular calcification. Treatment of 5/6 nephrectomized ApoE-/- mice with the TNFα neutralizing antibody or chemical Chaperones reduced aortic PERK-eIF2α-ATF4-CHOP signaling of the ER stress increased by CKD. This resulted in the inhibition of CKD-dependent vascular calcification.
  
  
  CONCLUSIONS
  These results suggest that TNFα induces the PERK-eIF2α-ATF4-CHOP axis of the ER stress response, leading to CKD-dependent vascular calcification.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO.
authors.forename: Masashi
authors.initials: M
authors.lastname: Masuda
authors.forename: Shinobu
authors.initials: S
authors.lastname: Miyazaki-Anzai
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.forename: Tabitha C
authors.initials: TC
authors.lastname: Ting
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
mesh_terms: D051701:Activating Transcription Factor 4 / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D008297:Male; D051379:Mice; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D061205:Vascular Calcification / Q000209:etiology*; D019892:eIF-2 Kinase / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase
keywords: ATF4; CHOP; TNFα; endoplasmic reticulum stress; vascular calcification