Proteasome Inhibition Represses Unfolded Protein Response and Nox4, Sensitizing Vascular Cells to Endoplasmic Reticulum Stress-Induced Death
Contribuinte(s) |
UNIVERSIDADE DE SÃO PAULO |
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Data(s) |
18/04/2012
18/04/2012
2011
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Resumo |
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. Methodology/Principal Findings: 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. Conclusion/Relevance: 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. Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[04/13683-0] Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)[09/54764-6] Instituto Nacional de Ciencia e Tecnologia de Processos Redox em BioMedicina (Redoxoma, INCT, CNPq) Fundacao Zerbini |
Identificador |
PLOS ONE, v.6, n.1, 2011 1932-6203 http://producao.usp.br/handle/BDPI/15065 10.1371/journal.pone.0014591 |
Idioma(s) |
eng |
Publicador |
PUBLIC LIBRARY SCIENCE |
Relação |
Plos One |
Direitos |
openAccess Copyright PUBLIC LIBRARY SCIENCE |
Palavras-Chave | #SMOOTH-MUSCLE-CELLS #NADPH OXIDASE ACTIVITY #OXIDATIVE STRESS #ER STRESS #NAD(P)H OXIDASE #MITOCHONDRIAL DYSFUNCTION #DISULFIDE-ISOMERASE #SIGNAL-TRANSDUCTION #CARCINOMA-CELLS #MESSENGER-RNA #Biology #Multidisciplinary Sciences |
Tipo |
article original article publishedVersion |