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

Author(s)

Amanso, Angelica M. ^[1] ; Debbas, Victor ^[1] ; Laurindo, Francisco R. M. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Med, Vasc Biol Lab, Heart Inst InCor, Sao Paulo - Brazil

• Document type: Journal article
• Source: PLoS One; v. 6, n. 1 JAN 26 2011.
• Web of Science Citations: 25

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. 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. (AU)

• FAPESP's process: 04/13683-0 - Coupling of stress of endoplasmatic reticule with oxidative stress in vascular cells via interaction between protein disulfide isomerase and NAD(p)H oxidase: role of thiol oxidoredutases
• Grantee: Francisco Rafael Martins Laurindo
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 09/54764-6 - Regulation of redox homeostasis and integrated stress response by Protein Disulfide Isomerase (PDI): mechanisms and role in the pathophysiology and therapy of vascular diseases
• Grantee: Francisco Rafael Martins Laurindo
• Support Opportunities: Research Projects - Thematic Grants