The peroxynitrite donor 3-morpholinosydnonimine activates Nrf2 and the UPR leading to a cytoprotective response in endothelial cells |
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Authors: | Mattart Laurine Calay Damien Simon Dorothy Roebroek Laura Roebroeck Laura Caesens-Koenig Ludmilla Van Steenbrugge Martine Tevel Virginie Michiels Carine Arnould Thierry Boudjeltia Karim Zouaoui Raes Martine |
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Affiliation: | a Research Unit of Cellular Biology, NARILIS (Namur Research Institute for Life Sciences), University of Namur (FUNDP), Belgiumb Laboratory of Experimental Medicine (ULB Unit 222), CHU Charleroi, ISPPC Hôpital Vésale, Montigny-Le-Tilleul, Belgium |
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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. |
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Keywords: | Peroxynitrite Endothelial cells Nrf2 Apoptosis LC3-II CHOP |
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