title: Peroxynitrite causes endoplasmic reticulum stress and apoptosis in human vascular endothelium: implications in atherogenesis.
abstract: OBJECTIVE
  Peroxynitrite, a potent oxidant generated by the reaction of NO with superoxide, has been implicated in the promotion of atherosclerosis. We designed this study to determine whether peroxynitrite induces its proatherogenic effects through induction of endoplasmic reticulum (ER) stress.
  
  
  RESULTS
  Human vascular endothelial cells treated with Sin-1, a peroxynitrite generator, induced the expression of the ER chaperones GRP78 and GRP94 and increased eIF2alpha phosphorylation. These effects were inhibited by the peroxynitrite scavenger uric acid. Sin-1 caused the depletion of ER-Ca2+, an effect known to induce ER stress, resulting in the elevation of cytosolic Ca2+ and programmed cell death (PCD). Sin-1 treatment was also found, via 3-nitrotyrosine and GRP78 colocalization, to act directly on the ER. Adenoviral-mediated overexpression of GRP78 in endothelial cells prevented Sin-1-induced PCD. Consistent with these in vitro findings, 3-nitrotyrosine was observed and colocalized with GRP78 in endothelial cells of early atherosclerotic lesions from apolipoprotein E-deficient mice.
  
  
  CONCLUSIONS
  Peroxynitrite is an ER stress-inducing agent. Its effects include the depletion of ER-Ca2+, a known mechanism of ER stress induction. The observation that 3-nitrotyrosine-containing proteins colocalize with markers of ER stress within early atherosclerotic lesions suggests that peroxynitrite contributes to atherogenesis through a mechanism involving ER stress.
authors.affiliation: Henderson Research Centre, McMaster University, Hamilton, Canada.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Dickhout
authors.forename: Gazi S
authors.initials: GS
authors.lastname: Hossain
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Pozza
authors.forename: Ji
authors.initials: J
authors.lastname: Zhou
authors.forename: Sárka
authors.initials: S
authors.lastname: Lhoták
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000502:physiology*; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D001057:Apolipoproteins E; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D020030:Nitric Oxide Donors; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; C002385:linsidomine; D008981:Molsidomine; D002118:Calcium