title: Proteasome inhibition represses unfolded protein response and Nox4, sensitizing vascular cells to endoplasmic reticulum stress-induced death.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) stress has pathophysiological relevance in vascular diseases and merges with proteasome function. Proteasome inhibition induces cell stress and may have therapeutic implications. However, whether proteasome inhibition potentiates ER stress-induced apoptosis and the possible mechanisms involved in this process are unclear.
  
  
  RESULTS
  Here we show that proteasome inhibition with MG132, per se at non-lethal levels, sensitized vascular smooth muscle cells to caspase-3 activation and cell death during ER stress induced by tunicamycin (Tn). This effect was accompanied by suppression of both proadaptive (KDEL chaperones) and proapoptotic (CHOP/GADD153) unfolded protein response markers, although, intriguingly, the splicing of XBP1 was markedly enhanced and sustained. In parallel, proteasome inhibition completely prevented ER stress-induced increase in NADPH oxidase activity, as well as increases in Nox4 isoform and protein disulfide isomerase mRNA expression. Increased Akt phosphorylation due to proteasome inhibition partially offset the proapoptotic effect of Tn or MG132. Although proteasome inhibition enhanced oxidative stress, reactive oxygen species scavenging had no net effect on sensitization to Tn or MG132-induced cell death.
  
  
  CONCLUSIONS
  These data indicate unfolded protein response-independent pathways whereby proteasome inhibition sensitizes vascular smooth muscle to ER stress-mediated cell death. This may be relevant to understand the therapeutic potential of such compounds in vascular disease associated with increased neointimal hyperplasia.
authors.affiliation: Vascular Biology Laboratory, Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, Brazil.
authors.forename: Angélica M
authors.initials: AM
authors.lastname: Amanso
authors.forename: Victor
authors.initials: V
authors.lastname: Debbas
authors.forename: Francisco R M
authors.initials: FR
authors.lastname: Laurindo
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000473:pathology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress; D061988:Proteasome Inhibitors; D011817:Rabbits; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D061988:Proteasome Inhibitors; D019255:NADPH Oxidases; D053148:Caspase 3