The peroxynitrite donor 3-morpholinosydnonimine activates Nrf2 and the UPR leading to a cytoprotective response in endothelial cells

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• 作者：Laurine  ; Mattart^a ;   ; ^{laurine.mattart@fundp.ac.be} ; Damien  ; Calay^a ; Dorothy  ; Simon^a ; Laura  ; Roebroeck^a ; Ludmilla  ; Caesens-Koenig^a ; Martine  ; Van Steenbrugge^a ; Virginie  ; Tevel^a ; Carine  ; Michiels^a ; Thierry  ; Arnould^a ; Karim Zouaoui  ; Boudjeltia^b ; Martine  ; Raes^a
• 关键词：Peroxynitrite ; Endothelial cells ; Nrf2 ; Apoptosis ; LC3-II ; CHOP
• 刊名：Cellular Signalling
• 出版年：2012
• 出版时间：January 2012
• 年：2012
• 卷：24
• 期：1
• 页码：199-213
• 全文大小：1323 K

文摘

Endothelial dysfunction is associated with the formation of peroxynitrite, described to be toxic. Recent data also suggests that peroxynitrite is able to activate the protective Nrf2 pathway and/or the unfolded protein response (UPR). The aim of our work was to study the response of human endothelial cells to 3-morpholinosydnonimine (SIN-1), a peroxynitrite donor, and to highlight the possible protective roles of Nrf2 or the UPR pathway in this response.

Immortal and primary human umbilical vein endothelial cells were exposed to SIN-1. SIN-1 incubation led to Nrf2 activation and to the overexpression of Nrf2-regulated genes, heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1. We also demonstrated that this defensive response protected cells against cell death induced by serum starvation, by reducing apoptosis (monitored by caspase-3 activity and DNA fragmentation) and favoring autophagosome formation, as evidenced by LC3-II accumulation. Interestingly, we observed an activation of the UPR, with a rapid and significant overexpression of CHOP in serum starved cells stimulated with SIN-1. While siRNA mediated knockdown of CHOP had no effect on DNA fragmentation, the invalidation of Nrf2 or HO-1 by siRNA strongly increased DNA fragmentation, but also reinforced the SIN-1-induced LC3-II accumulation.

This study shows that peroxynitrite, at least at sublethal concentrations and within a narrow concentration range, could exert protective effects on endothelial cells by modulating the balance between autophagy and apoptosis, through Nrf2-dependent pathways.