Abstract
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.
Original language | English |
---|---|
Pages (from-to) | 199-213 |
Number of pages | 15 |
Journal | Cellular Signalling |
Volume | 24 |
Issue number | 1 |
DOIs | |
Publication status | Published - 2012 |
Fingerprint
Dive into the research topics of 'The peroxynitrite donor 3-morpholinosydnonimine activates Nrf2 and the UPR leading to a cytoprotective response in endothelial cells'. Together they form a unique fingerprint.Equipment
-
Genetics - Genomics
Gillet, N. (Manager)
Technological Platform Genetics - GenomicsFacility/equipment: Technological Platform
-
Light Microscopy
Renard, H.-F. (Manager), Forrester, A. (Manager), Demazy, C. (Other) & Ledoux, B. (Manager)
Technological Platform Morphology - ImagingFacility/equipment: Equipment
-
Morphology - Imaging
Cecchet, F. (Manager) & Renard, H.-F. (Manager)
Technological Platform Morphology - ImagingFacility/equipment: Technological Platform