Targeting the Endoplasmic Reticulum Unfolded Protein Response to Counteract the Oxidative Stress‐Induced Endothelial Dysfunction

Abstract

In endothelial cells, the tight control of the redox environment is essential for the maintenance of vascular homeostasis. The imbalance between ROS production and antioxidant response can induce endothelial dysfunction, the initial event of many cardiovascular diseases. Recent studies have revealed that the endoplasmic reticulum could be a new player in the promotion of the pro- or antioxidative pathways and that in such a modulation, the unfolded protein response (UPR) pathways play an essential role. The UPR consists of a set of conserved signalling pathways evolved to restore the proteostasis during protein misfolding within the endoplasmic reticulum. Although the first outcome of the UPR pathways is the promotion of an adaptive response, the persistent activation of UPR leads to increased oxidative stress and cell death. This molecular switch has been correlated to the onset or to the exacerbation of the endothelial dysfunction in cardiovascular diseases. In this review, we highlight the multiple chances of the UPR to induce or ameliorate oxidative disturbances and propose the UPR pathways as a new therapeutic target for the clinical management of endothelial dysfunction.

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

“…In particular, oxidative stress can induce mtDNA base modifications, abasic sites, single-and double-strand breaks, point mutations, large-sized deletions, and changes in mtDNA content [113,114]. While it is well-known that mitochondria produce ROS at the level of complexes I and III [115], ER is also a relevant oxidant source mainly produced by members of cytochrome P450 and nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase 4 (NOX4) [116,117].…”

“…Similar to the mitochondrial-lysosomal axis, contacts between mitochondria and the ER can mediate bidirectional signaling to determine the cell's fate during aging. The transmembrane protein kinase RNA-like ER kinase (PERK), a member of the ER stress/unfolded protein response (UPR) machinery [117], enables ER-mitochondrial tethering during ER stress to facilitate Ca 2+ influx and ROS-dependent mitochondrial-mediated apoptosis [118]. Moreover, a strongly oxidizing environment around ER-mitochondrial contacts modulates organelle apposition through the mitogen-activated protein kinase (MAPK)-dependent control of mitochondrial mobility [119].…”

Unfolded protein response regulates P53 expression in the pulmonary endothelium

“…However, the outcomes appear to be tissue‐specific, since it was shown that the endoplasmic reticulum stress stimulates P53 expression through nuclear factor‐κB (NF‐κB) activation, while others have demonstrated the opposite effects in different experimental systems . Several studies have shown the correlation of endoplasmic reticulum stress and UPR to endothelial dysfunction in both animal and cellular models . To the best of our knowledge, the present study is the first to report that the modulation of the UPR activation by a variety of chemical UPR inducers and suppressors regulate the expression of P53 in bovine endothelial cells.…”

“…A mild induction of that element is associated with anti‐inflammatory, protective activities. It was suggested that targeting the unfolded protein response element counteracts the oxidative stress‐induced endothelial dysfunction . A subcytotoxic dose of subtilase cytotoxin prevented the LPS‐induced inflammatory responses, depending on its capacity to induce the UPR .…”

“…UPR activation induced P53, while its suppression reduced the levels of this transcription factor. Since a mild UPR induction has been previously shown to be associated with the repair of the endothelium, it may serve as well as a potential therapeutic strategy towards ALI/ARDS.…”