Proteasome Inhibition Represses Unfolded Protein Response and Nox4, Sensitizing Vascular Cells to Endoplasmic Reticulum Stress-Induced Death


Autoria(s): AMANSO, Angelica M.; DEBBAS, Victor; LAURINDO, Francisco R. M.
Contribuinte(s)

UNIVERSIDADE DE SÃO PAULO

Data(s)

18/04/2012

18/04/2012

2011

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

http://dx.doi.org/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